Successful Drug Discovery, Volume 5 E-Book
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- Herausgeber: Wiley-VCH GmbH
- Kategorie: Wissenschaft und neue Technologien
- Sprache: Englisch
Filled with unique insights into current drugs that have made it to the marketplace
In the fifth volume of Successful Drug Discovery, the inventors and primary developers of drugs that made it to the market tell the story of the drug�s discovery and development. Case studies of drugs from different therapeutic fields reveal the all-too-often unpredictable path from the first drug candidate molecule to the successfully marketed drug. In addition, this new volume addresses overarching topics for drug discovery, such as drug discovery in academia, and discusses currently important classes of small molecule as well as biological drugs. Comprehensive in scope, the book�s nine chapters provide a representative cross-section of the present-day drug development effort.
The authoritative fifth volume is filled with relevant data and chemical information, as well as the insight and experience of the best contemporary drug creators. This important volume:
- Puts the focus on recently introduced drugs that have not yet made it into standard textbooks or general references
- Contains information and insight that is new and often not even available from the primary literature
- Reveals what it takes to successfully develop a drug molecule that has made it all the way to the market
- Is endorsed and supported by the International Union of Pure and Applied Chemistry (IUPAC)
Written for medicinal chemists, pharmaceutical chemists, organic chemists, Successful Drug Discovery, Volume Five reveals the most recent techniques used by drug innovators in the drug development process.
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Veröffentlichungsjahr: 2021
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Table of Contents
Cover
Title Page
Copyright
Advisory Board Members
Preface
Part I: General Aspects
1 Drug Discovery in Academia
1.1 Introduction
1.2 Repurposing Drugs
1.3 Pregabalin
1.4 Natural Product‐Derived Drug Discovery
1.5 Biologic Drugs
1.6 Conceptionally New Small Molecule Drugs
1.7 Sweet Spot for Academic Drug Discovery
List of Abbreviations
References
Biography
2 From Degraders to Molecular Glues: New Ways of Breaking Down Disease‐Associated Proteins
2.1 Introduction
2.2 Definition and Historical Development of Degraders
2.3 The Ubiquitin–Proteasome System and Considerations of E3 Ligases
2.4 General Design Aspects
2.5 Differentiation of the Degrader Technology to Traditional Approaches
2.6 Potential Disadvantages and Limitations of Degraders
2.7 Molecular Glue‐like Degraders and Monovalent Degraders
2.8 Future Directions (Status Q3 2020)
2.9 Summary and Conclusions
Acknowledgments
List of Abbreviations
References
Biographies
Part II: Drug Class Studies
3 GLP‐1 Receptor Agonists for the Treatment of Type 2 Diabetes and Obesity
3.1 Introduction
3.2 GLP‐1 Biology
3.3 Ex4‐Based Analogues
3.4 GLP‐1 Based Analogues
3.5 Co‐agonists
3.6 Summary
List of Abbreviations
References
Biographies
4 Recent Advances on SGLT2 Inhibitors: Synthetic Approaches, Therapeutic Benefits, and Adverse Events
4.1 Introduction
4.2 The Mechanism of Action of SGLT2 Inhibitors
4.3 Synthetic Approaches to Gliflozins
4.4 Clinical Benefits of SGLT2 Inhibitors
4.5 Safety Profile and Particularly Relevant Adverse Events Associated with SGLT2 Inhibitors
4.6 Application of SGLT2 Inhibitors in Type 1 Diabetes
4.7 Conclusions
Acknowledgments
References
Biographies
5 CAR T Cells: A Novel Biological Drug Class
5.1 Introduction
5.2 A Brief History of Cell‐Based Therapies
5.3 Genetically Engineered T Cell Therapy Products
5.4 CAR T Cells: The Living Drug
5.5 Translation from Laboratory Innovation to Approved Therapy
5.6 Future Directions and CAR T Programs to Consider
5.7 Additional Resources for Supplementary Information on Cellular Therapies, Including Regulations, Notifications, and Guidelines
References
Biographies
6 CGRP Inhibitors for the Treatment of Migraine
6.1 Introduction
6.2 The Overall Physiological Role of CGRP
6.3 The Role of CGRP in the Gut
6.4 What Is the Role of CGRP in Migraine?
6.5 Role of CGRP Antagonists in Other Indications
6.6 Conclusions
List of Abbreviations
References
Biographies
Part III: Case Studies
7 Discovery and Development of Emicizumab (HEMLIBRA
®
): A Humanized Bispecific Antibody to Coagulation Factors IXa and X with a Factor VIII Cofactor Activity
7.1 Introduction
7.2 Preclinical Experience with Emicizumab
7.3 Clinical Experience with Emicizumab
7.4 Conclusions
Acknowledgments
Conflict of Interests
References
Biographies
8 Discovery and Development of Ivosidenib (AG‐120: TIBSOVO
®
)
8.1 Introduction
8.2 Crystal Structure of IDH1
8.3 Search for mIDH1 Inhibitors
8.4 Hit to Lead Exploration
8.5 Lead Optimization: Discovery of AG‐120
8.6 Synthesis of AG‐120
8.7 Preclinical Characterization of AG‐120
8.8 Ivosidenib Clinical Studies
8.9 Conclusions
References
Biographies
9 The Discovery of Kisqali
®
(Ribociclib): A CDK4/6 Inhibitor for the Treatment of HR+/HER2− Advanced Breast Cancer
9.1 Disease Background
9.2 Target Background and Validation: The Cell Cycle
9.3 Commencement of Drug Discovery Efforts
9.4 Fragment‐based Approach
9.5 Cross‐Screening of Existing Kinase Assets Leading to Ribociclib
9.6 Combination Treatments with Ribociclib
9.7 Early‐Phase Clinical Studies
9.8 Phase 3 Clinical Studies
9.9 Conclusions
Acknowledgments
References
Biographies
Index
End User License Agreement
List of Tables
Chapter 2
Table 2.1 Selected examples of different target types that have been successf...
Chapter 4
Table 4.1 Summary of the first results of randomized controlled trials testin...
Chapter 5
Table 5.1 Ongoing CAR T cell clinical trials.
Chapter 6
Table 6.1 Summary of CGRP/CGRP‐R mABs.
Chapter 7
Table 7.1 Annualized bleeding rates for bleeding events treated with coagulat...
Chapter 8
Table 8.1 R
1
Initial SAR based on the enzymatic activity of derivatives of 2,
Table 8.2 R
2
Initial SAR based on the enzymatic activity of derivatives of
N
‐...
Table 8.3 R
3
initial SAR based on the enzymatic activity of the phenyl‐glycin...
Table 8.4 R
4
Initial SAR based on the enzymatic activity of derivatives of 2,
Table 8.5 Cell potency of selected potent
N
‐phenyl glycine analogues.
Table 8.6 Second round SAR optimization: enzymatic activity, cellular potency...
Table 8.7 Reduction of hPXR activation leading to AG‐120.
Table 8.8 Biochemical and Cellular Profiling of
AG‐120
.
Table 8.9
In vitro
ADME and
in vivo
PK properties of
AG‐120
.
List of Illustrations
Chapter 1
Figure 1.1 FDA drug approvals from 1990 to 2019.
Figure 1.2 S‐Lost, N‐Lost, modern agents.
Figure 1.3 GABA biology.
Figure 1.4 3‐Me‐GABA analogues synthesized by Andruskiewicz and Silverman.
Figure 1.5 Lead structures isolated from natural sources.
Figure 1.6 Camptothecin and approved derivatives.
Figure 1.7 Taxol derivatives.
Figure 1.8 Semisynthetic approaches to Taxol.
Figure 1.9 Epothilone derivatives.
Figure 1.10 Structures of halichondrin B, eribulin mesylate, and E7130.
Figure 1.11 Seeberger's flow synthesis of artemisinin and artemether, essent...
Figure 1.12 Epoxomicin binding to the 20S‐ribosome.
Figure 1.13 From epoxomicin to carfilzomib.
Figure 1.14 Structures of DMSO and hydroxamic acid derivatives leading to th...
Figure 1.15 Structures of antiviral compounds developed by Hóly and De Clerc...
Figure 1.16 HIV protease inhibitors.
Figure 1.17 Kinase inhibitors developed by Sugen.
Chapter 2
Figure 2.1 Degrader‐mediated targeted protein degradation (illustrated with ...
Figure 2.2 Historical development of degraders since their first report in 2...
Figure 2.3 Structures of IMiDs binding to E3 ligase CRBN (for more details o...
Figure 2.4 Structure of VHL‐1, an optimized binder to E3 ligase VHL.
Figure 2.5 Increasing number of publications on degraders.
Figure 2.6 Structures of ligands that can be used to design degraders to rec...
Figure 2.7 General strategy using the Huisgen reaction for parallel synthesi...
Figure 2.8 The (un)druggable genome and number of potential targets.
Figure 2.9 Oversaturation of the system with degrader molecules leads to the...
Figure 2.10 Crystal structures of natural product molecular glues: Calcineur...
Figure 2.11 A comparison of binary versus ternary complex formation approach...
Figure 2.12 MoA of (a) Thalidomide, (b) Pomalidomide and (c) Lenalidomide: C...
Figure 2.13 Molecular glue‐like degraders of the next generation: (a) CC‐885...
Figure 2.14 Examples of monovalent degraders, degradation tails if identifie...
Chapter 3
Figure 3.1 Human proglucagon (as encoded on complementary DNA). GRPP, glicen...
Figure 3.2 Peptide sequence of GLP‐1 (1‐37), GLP‐1 (7‐37), GLP‐1 (7‐36)‐amid...
Figure 3.3 (a) Cryo EM structure of GLP‐1R in complex with GLP‐1 and the sig...
Figure 3.4 Timeline for GLP‐1 discovery and compounds approved by the Americ...
Figure 3.5 The primary structure of human GLP‐1 and Ex4.
Figure 3.6 The primary structure of lixisenatide.
Figure 3.7 Schematic representation of the structure of efpeglenatide [30]....
Figure 3.8 Schematic representation of pegylated loxenatide: mPEG, methoxy p...
Figure 3.9 The structure of liraglutide.
Figure 3.10 The structure of semaglutide.
Figure 3.11 The primary structure of taspoglutide.
Figure 3.12 Schematic representation of albiglutide.
Figure 3.13 Schematic diagram of dulaglutide. The GLP‐1 analog, linker regio...
Figure 3.14 Sequence of GLP‐1, Ex4, glucagon, oxyntomodulin, GIP, NNC0090‐27...
Figure 3.15 Lead structure of 11‐mer GLP‐1R agonists from Bristol‐Myers Squi...
Chapter 4
Figure 4.1 Schematic representation of the mechanism of action of SGLT2 inhi...
Figure 4.2 Structure of the marketed gliflozins or candidates in phase III c...
Figure 4.3 Structure of the dual inhibitors phlorizin and licogliflozin, and...
Scheme 4.1 The first synthesis of dapagliflozin developed by Washburn and co...
Scheme 4.2 Synthesis of dapagliflozin (
1
) developed by Gou and coworkers [19...
Scheme 4.3 Synthesis of dapagliflozin developed by Walczak and coworkers [20...
Scheme 4.4 Synthetic route of dapagliflozin reported by Yu and coworkers [22...
Scheme 4.5 Synthetic approach of sotagliflozin (
2
) developed by Goodwin et a...
Scheme 4.6 Synthetic pathway to sotagliflozin (
2
) developed by Li and cowork...
Scheme 4.7 Synthesis of empagliflozin (
3
) following the synthetic pathway re...
Scheme 4.8 Synthesis of benzyl‐protected empagliflozin
45
by reaction of iod...
Scheme 4.9 Synthesis of empagliflozin analogue
54
[28].
Scheme 4.10 Synthetic route of bexafloglizin (
4
) developed by Sun and cowork...
Scheme 4.11 Synthesis of luseogliflozin (
5
) by Kakinuma et al. [32]. (a) Syn...
Scheme 4.12 Tofogliflozin synthesis reported by Chugai Pharmaceuticals [34]....
Scheme 4.13 Preparation of the tofogliflozin's aglycone [38].
Scheme 4.14 Preparation of glycone
90
[38].
Scheme 4.15 Synthesis of tofogliflozin (
6
) [38].
Scheme 4.16 Synthesis of ertugliflozin (
7
) carried out by Triantakonstanti e...
Scheme 4.17 Synthesis of ipragliflozin (
8
) by Zhou and coworkers [45]. Licen...
Scheme 4.18 Canagliflozin (
9
) synthesis according to Nomura et al. [48].
Scheme 4.19 Canagliflozin (
9
) synthesis according to Nakamura and coworkers ...
Scheme 4.20 Patented synthesis by Optimus Drugs Pvt. Ltd of canagliflozin (
9
Scheme 4.21 Improved process for the synthesis of canagliflozin (
9
) develope...
Scheme 4.22 Total synthesis of remogliflozin etabonate (
10
) by Kobayashi et ...
Figure 4.4 Benefits versus risks of treatment with SGLT2 inhibitors.
Chapter 5
Figure 5.1 T cell receptor and costimulatory activation or inhibition of T c...
Figure 5.2 A comparison of the basic structure of engineered TCR and CAR con...
Figure 5.3 CAR design and evolution. CAR molecules consist of an extracellul...
Figure 5.4 Cellular kinetics of CART19 cells in leukemia patients. CART19 ex...
Figure 5.5 Vein‐to‐vein workflow for the clinical manufacture of lentiviral ...
Figure 5.6 Potential mechanisms of CAR T cell therapy in cancer. Cancer cell...
Chapter 6
Figure 6.1 Structures of selected small‐molecule CGRP‐RA. (a) Telcagepant, (...
Figure 6.2 Comparison of the placebo subtracted headache improvement at two ...
Figure 6.3 Efficacy at early time points in the phase 2 chronic migraine tri...
Chapter 7
Figure 7.1 (a) FVIIIa consists of the A1 subunit, the A2 subunit, and the li...
Figure 7.2 Flow of process to identify the lead bispecific antibody (BS15). ...
Figure 7.3 Multidimensional optimization flow to generate the bispecific ant...
Figure 7.4 Schematic illustration of the emicizumab molecule. CDR, complemen...
Chapter 8
Figure 8.1 Generation of R(−)‐2‐hydroxyglutarate by mIDH1.
Figure 8.2 Structural Analysis of WT vs mIDH1 Proteins. Left panels show Wi...
Figure 8.3 Inhibition of the mIDH1 R132H enzyme reaction via a diaphorase/re...
Figure 8.4 HTS
Hit 1
and retrosynthetic analysis of the 2,
N
‐diphenyl glycine...
Figure 8.5 Key structural elements accounting for the enzymatic activity of ...
Scheme 8.1 (a) Synthesis of derivatives of 2,
N
‐diphenyl glycine via the Ugi ...
Figure 8.6 Tumor 2‐HG inhibition following one (a) and three BID doses (b) o...
Figure 8.7 Tumor 2‐HG concentration following single QD dose of AGI‐14100 in...
Scheme 8.2 Synthesis of AG‐120 via the Ugi reaction ([20]; supporting inform...
Figure 8.8 Tumor 2‐HG concentration and
AG‐120
plasma concentration fo...
Figure 8.9
Ex vivo
treatment with
AG‐120
reduces 2HG in primary patien...
Figure 8.10
Ex vivo
treatment with
AG‐120
increases differentiation ma...
Figure 8.11 “Swim plot” showing each patient and treatment outcome of the be...
Chapter 9
Figure 9.1 A simplified model of the cell cycle showing cyclin‐CDK complexes...
Figure 9.2 The CDK4/6 pathway and oncogenic mutations.
Figure 9.3 Structure‐based optimization of a fragment hit.
Figure 9.4 Evolution of a fragment‐based series.
Figure 9.5 Optimization of an existing kinase asset leading to ribociclib.
Figure 9.6 Crystal structure of ribociclib bound to cyclin D1‐CDK4: ribocicl...
Figure 9.7 Ribociclib arrests the cell cycle exclusively in G1: JeKo‐1 mantl...
Figure 9.8 Ribociclib given orally once daily causes dose‐dependent tumor re...
Figure 9.9 Activity of ribociclib in combination with the aromatase inhibito...
Guide
Title Page
Table of Contents
Begin Reading
Index
WILEY END USER LICENSE AGREEMENT
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Successful Drug Discovery
Volume 5
Edited by
János FischerChristian KleinWayne E. Childers
Editors
János Fischer
Richter Co., Plc.
Pharma Research
Gyömröi ut 19/21
1103 Budapest
Hungary
Christian Klein
Roche Innovation Center Zurich
Cancer Immunotherapy Discovery
Wagistrasse 10
8952 Schlieren
Switzerland
Wayne E. Childers
Temple University School of Pharmacy
Moulder Ctr. for Drug Discovery Res.
3307 N Broad Street
PA
United States
Cover
Supported by the
International Union of Pure and Applied Chemistry (IUPAC)
Chemistry and Human Health Division
PO Box 13757
Research Triangle Park, NC 2770‐3757
USA
All books published by Wiley‐VCH are carefully produced. Nevertheless, authors, editors, and publisher do not warrant the information contained in these books, including this book, to be free of errors. Readers are advised to keep in mind that statements, data, illustrations, procedural details or other items may inadvertently be inaccurate.
Library of Congress Card No.:
applied for
British Library Cataloguing‐in‐Publication Data
A catalogue record for this book is available from the British Library.
Bibliographic information published by the Deutsche Nationalbibliothek
The Deutsche Nationalbibliothek lists this publication in the Deutsche Nationalbibliografie; detailed bibliographic data are available on the Internet at <http://dnb.d-nb.de>.
© 2021 WILEY‐VCH GmbH, Boschstr. 12, 69469 Weinheim, Germany
All rights reserved (including those of translation into other languages). No part of this book may be reproduced in any form – by photoprinting, microfilm, or any other means – nor transmitted or translated into a machine language without written permission from the publishers. Registered names, trademarks, etc. used in this book, even when not specifically marked as such, are not to be considered unprotected by law.
Print ISBN: 978‐3‐527‐34754‐4
ePDF ISBN: 978‐3‐527‐82685‐8
ePub ISBN: 978‐3‐527‐82686‐5
oBook ISBN: 978‐3‐527‐82687‐2
Advisory Board Members
Jonathan Baell
(Monash University)
Gabriele Costantino
(University of Parma)
Jagath Reddy Junutula
(ModMab Therapeutics)
Kazumi Kondo
(Otsuka)
Roberto Pellicciari
(TES Pharma S.r.l.)
David Rotella
(Montclair State University)
Preface
The International Union of Pure and Applied Chemistry (IUPAC) supports the publication of the book series Successful Drug Discovery as projects. In these books, experts and key inventors describe and analyze different aspects of drug discovery.
The fifth volume of Successful Drug Discovery has the same structure as the previous volumes. New drug discoveries will be discussed in three parts: Part I: General Aspects, Part II: Drug Class Studies, and Part III: Case Studies encompassing both small‐molecule drugs and biologics.
The editors thank the advisory board members: Jonathan Baell (Monash University), Gabriele Costantino (University of Parma), Jagath R. Junutula (ModMab Therapeutics), Kazumi Kondo (Otsuka Pharmaceutical), Roberto Pellicciari (TES Pharma), and David Rotella (Montclair State University). Special thanks go to the following reviewers who helped both the authors and the editors: John M. Beals, András Kern, Béla Kiss, Thomas Luebbers, Gerd Schnorrenberg, William N. Washburn, and Peng Wu. Special thanks are due to Juergen Stohner for his review from the viewpoint of the IUPAC Interdivisional Committee on Terminology, Nomenclature, and Symbols (ICTNS).
Part I: General Aspects
Oliver Plettenburg (University of Hannover and Helmholtz Centre Munich) affords an overview on drug discoveries originating from academic research. The chapter covers both small‐molecule drugs and biologics as well as some natural product‐derived drugs. The chapter testifies to how drug discovery has become vital and indispensable discipline at many academic institutions.
Ynonne Alice Nagel, Adrian Britschgi, and Antonio Ricci (Roche) summarize new ways of breaking down disease‐associated proteins. Targeted protein degradation via so‐called PROTACS and other approaches now allows researchers to modulate previously undruggable target proteins.
Part II: Drug Class Studies
Lars Linderoth, Jacob Kofoed, János T. Kodra, Steffen Reedtz‐Runge, and Thomas Kruse (Novo‐Nordisk) review the very important drug class of GLP‐1R agonists for the treatment of diabetes type 2. Since the discovery of GLP‐1 in the 1980s and the launch of the first GLP‐1R agonist‐based therapeutics, multiple development paths have arisen for this successful class of drugs.
Ana Marta de Matos, Patrcia Calado, William Washburn, and Amélia Pilar Rauter (University of Lisbon) report on another very important drug class for the treatment of diabetes type 2: SGLT2 (sodium‐glucose cotransporter‐2) inhibitors. The pioneer drug dapagliflozin initiated drug research resulting in several new and successful analogues. The chapter focuses on recent synthetic advances and clinical data for this class of drugs.
Whitney Gladney, Julie Jadlowsky, Megan M. Davis, and Andrew Fesnak (University of Pennsylvania) review the field of cell‐based therapy in a chapter on “CAR T Cells: A Novel Biological Drug Class.” Their chapter describes the first cell‐based gene therapy treatment used for the treatment of relapsed acute lymphoblastic leukemia.
Sarah Walter and Marcelo E. Bigal (Antiva Biosciences and Ventus Therapeutics) describe CGRP (calcitonin gene‐related peptide) inhibitors for the treatment of migraine, which represent a new class of drugs consisting of both small‐molecule drugs and biologics.
Part III: Case Studies
Takehisa Kitazawa, Koichiro Yoneyama, and Tomoyuki Igawa (Chugai Pharmaceuticals) provide a case study of emicizumab, a humanized bispecific antibody to coagulation factors IXa and X that also possesses factor VIII cofactor activity. Emicizumab (HEMLIBRA™) was approved by US FDA in 2017 for treatment of hemophilia A.
Zenon D. Konteatis and Zhihua Sui (Agios Pharmaceuticals) describe the discovery and development of ivosidenib (Tibsovo™), which was approved by US FDA in 2019 for newly diagnosed acute myeloid leukemia with a susceptible IDH1 mutation.
Christopher T. Brain, Rajiv Chopra, Sunkyu Kim, Steven Howard, and Moo Je Sung (Novartis) recount the discovery of ribociclib (Kisqali™), a CDK4/6 inhibitor for the treatment of HR positive/HER2 negative advanced brain cancer. Ribociclib was approved by the US FDA in 2017 for use in combination with an aromatase inhibitor.
The editors and authors thank Wiley‐VCH and personally Dr. Frank Weinreich and Katherine Wong for the excellent collaboration.
János Fischer
Budapest
Wayne E. Childers
Philadelphia
Christian Klein
Zürich
June 2020
Part IGeneral Aspects
1Drug Discovery in Academia
Oliver Plettenburg1
1Helmholtz Zentrum München (GmbH), German Research Center for Environmental Health, Institute of Medicinal Chemistry, Ingolstädter Landstr. 1, D‐85764, Neuherberg, Germany
2Leibniz Universität Hannover, Center for Biomolecular Research, Institute of Organic Chemistry, Schneiderberg 1b, D‐30167, Hannover, Germany
1.1 Introduction
It is estimated that the global pharmaceutical industry invested more than US$ 1.36 trillion in the decade from 2007 to 2017, and predicted annual spending is assumed to totally sum up to 181 billion for the period to 2020 [1]. At the end of 2019, the 10 largest pharmaceutical companies represented a market capitalization of approximately US$ 1.68 trillion [2].
The tremendous advances in science starting in the 1990s stipulated hopes that the discovery of new medicines would soon turn into an engineerable process. The decryption of the human genome provided a plethora of new target opportunities for exploitation, and the availability of large screening collections, efficient miniaturized high‐throughput screening technologies, and computer‐assisted methods for hit generation suggested that generation of reasonable lead structures should be feasible for many of these targets. Furthermore, cellular models for early prediction of metabolic liabilities and toxicological risks enhanced the optimization of drug‐like properties. However, after 30 years, these hopes did not turn into reality; the number of approved drugs remained approximately constant, at least for the period from 1989 to 2013. In 2019, the Food and Drug Administration (FDA) approved 47 new drugs, 9 of which are biologics (Figure 1.1) [3]. It is an interesting observation that despite the trend to focus research on biologics and small‐molecule drug business was said to be dead for several years, the fraction of annual new biological drug approvals is still stagnating at about 25 %.
In an article published in 2011, Stevens [4] analyzed the contributions of publicly funded organizations to current approval rates over a period of 40 years. It is remarkable to note that about 9 % of all approvals (143/1541) were enabled or at least facilitated by public funding. If one compares the contributions for new molecular entities, the rate rises to 13.3 % (64 out of 483). For new molecular entities that have been granted priority review, the report cites an impressive 21.1 % (44 out of 209). In a recent study, Nayak et al. [5] confirmed the significance of pharmaceutical research driven by universities and clinical centers. They thoroughly analyzed FDA drug approvals between 2008 and 2019, considering also patent information. Among the 248 approvals of new molecular entities, they identified significant contributions by publicly funded organizations for 62 (25 %) of them. It is puzzling that pharmaceutical ventures with their highly skilled scientists and an infrastructure that is capable of accessing virtually unlimited funds dedicated solely to the purpose of drug discovery did not perform better than these figures tell us. This is even more surprising in light of the fact that provision of new drugs to the pipeline is obviously a vital task in order to maintain the company going in the future and patent lifetime of approved therapies is clearly very limited.
Figure 1.1 FDA drug approvals from 1990 to 2019.
Source: Data from Mullard [3].
Independent development of a drug to a marketed product is clearly out of scope for any academic. It is estimated that out of pocket costs for approval of a single drug can amount to US$ 1.3 billion, with the majority of this budget being consumed by clinical trials. Also the process needs oversight and management by experienced clinical scientists to optimally set up the studies in order to ensure that a potential beneficial outcome will not be a victim of an underpowered study group or that the selection of the patient population was not optimal.
However, when the clinical trial starts, the selection process of the therapeutic moiety is already completed and the decision on target and approach is taken, from that point on it is the task of the clinicians to see if the generated hypothesis will hold true.
However, academics provide important contributions to drug discovery, using their specific strengths. These can be based on curiosity, expert knowledge in specific areas, exploitation of surprising findings, stimulating follow‐up research, and interdisciplinary research resulting from different academic laboratories teaming up, for instance. Different examples of how these specific strengths can lead to successful drug discovery will be discussed throughout this chapter.
1.2 Repurposing Drugs
One contribution ideally suited for academic research is the quest for new indications.
As approved drugs are openly commercially available, researchers, particularly scientists in clinical centers, can – based on patient derived data – generate hypotheses and probe them in a straightforward manner. In this context drug repurposing has attracted a lot of attention as the approach is very straightforward, and the resulting drug has already been demonstrated to be safe, bioavailable, and well tolerated in humans.
Often, this approach is guided by careful observation of disease‐accompanying factors and interpretation of the underlying pathology. In particular, changes of symptoms in patients suffering from more than one disease may provide interesting starting points for developing new hypotheses. An example is rituximab, which first was developed for the treatment of cancer. Its discovery will be discussed in more detail during the course of the chapter. Edwards et al. proposed that self‐perpetuating B‐lymphocytes may play a key role in driving progression of rheumatoid arthritis (RA) and autoimmune diseases [6]. They hypothesized that a CD20 (cluster of differentiation 20) targeted therapeutic, capable of specifically depleting this population of B‐cells, may represent an interesting therapeutic option. In 1999, a first case report of a patient suffering from non‐Hodgkin's lymphoma in association with inflammatory arthropathy appeared [7]. Within weeks of treatment with a monoclonal anti‐CD20 antibody, significant improvement of joint pain was observed, and three months later, the patient was virtually symptom‐free and capable of walking distances of 5 miles per day. In a following phase 2 study, positive results of rituximab in patients with RA were demonstrated, [8] followed by further trials. After being able to demonstrate convincing beneficial effects, rituximab was approved for treatment of RA in combination with methotrexate in 2006.
1.2.1 Thalidomide Derivatives
A second example is the utilization of thalidomide, lenalidomide, and pomalidomide for treatment of leprosy and various cancers. After the infamous and tragic history of thalidomide, it would be nearly impossible for any researcher in a big pharmaceutical venture to revive this drug. Being approved in Germany in 1957, thalidomide was frequently used for treatment of morning sickness. As the side effect profile seemed very favorable, it was frequently used by pregnant women. However, in 1961 reports on increased birth defects were reported, which were finally linked to thalidomide. These defects led to a significantly increased mortality at birth as well as to limb deformations, heart problems, and other side effects. It is estimated that more than 10 000 children were born with limb defects. The retraction of the drug from the European market led to introduction of a requirement for more stringent characterization of drug safety during the registration process. Teratogenicity is now one of the flags that will lead to exclusion of a drug from almost any optimization program, as it is difficult to rule out any erroneous use in women of child‐bearing age. However, by 1964, only three years after market withdrawal, Jacob Sheskin from Hadassah University in Jerusalem used thalidomide to treat patents in serious condition of leprosy [9]. In his original publication, Sheskin referred to administering thalidomide to six leprosy patients as a sedative drug; however, to his surprise the disease condition of all six patients improved. The initial study was followed by multiple comparative studies and the clinical benefit, in particular with respect to onset of action, and good tolerability became evident. Thalidomide was finally approved for treatment of leprosy in 1998.
Further research by Judah Folkman's laboratory at Children's Hospital at Harvard Medical School demonstrated that thalidomide effectively inhibited angiogenesis induced by fibroblast growth factor 2, offering a potential mechanistic explanation for the observed limb deformations [10]. Angiogenesis, however, is a hallmark of tumor growth, so in 1997 a trial was started [11] to examine the efficacy of treatment with thalidomide in patients with multiple myeloma, a hematological cancer that was not curable by conventional chemotherapy. A response rate of 32 % was observed. Actually, a first oncology clinical trial of thalidomide had already been performed as early as 1965. Olsen et al. [12] treated 21 patients suffering from various types of advanced cancers with thalidomide. Overall no inhibitory effect of tumor progression was observed in this study. The authors described subjective palliation in one third of patients. Albeit no tumor regression was observed, the authors noted a possible temporary slowing of rapidly progressing cancer in two patients. Interestingly, one of them was suffering from multiple myeloma.
1.2.2 Chemotherapy: Nitrogen Mustards
Another example of drug repurposing is the establishment of chemotherapy for treatment of cancer. Mustard gas was one of the deadliest and most detestable weapons used in World War I, leading to the death of hundreds of thousands of people. Stimulated by findings in medical records of soldiers exposed to mustard gas, which noted that significant changes in the blood composition were observed (notably a pronounced leucopenia), [13] Milton Winternitz, a chemist, teamed up with two pharmacologists at Yale University, Louis Goodman and Alfred Gilman. They decided to investigate potential therapeutic effects of chemical warfare agents for potential treatment of cancer (Figure 1.2). While sulfur lost (S‐lost) proved too volatile for therapeutic use, the corresponding nitrogen derivative (N‐lost) was more amendable to administration. The hydrochloride salt was significantly safer to handle and solutions for injections could be readily obtained before the anticipated use by dissolution in sterile saline. In a mouse model of lymphosarcoma, rapid tumor regression was observed, albeit the authors noted that required doses were close to toxic levels and tumor reoccurrence was inevitable [14]. However, a first human patient was treated on 27 August 1942, a date that can be regarded as the birth of chemotherapy. J.D. (only the initials of said patient are known today) suffered from advanced non‐Hodgkin's lymphoma [15]. He was already treated with radiation therapy, but the tumor still spread and left the patient in a very severe condition. He thus volunteered to participate in an exploratory study, and indeed daily injections of the drug were able to reverse the symptoms. Rapid tumor regression was observed and his overall condition improved significantly. Unfortunately, the effects were relatively short‐lived. A second series of injections was still able to provide some relief from tumor reoccurrence, but a third round of treatment could not improve the patient's condition any more, and J.D. died 96 days after the first injection. However, his lifespan was likely significantly prolonged, and these results spurred further clinical investigation [16]. Overall, beneficial effects have been observed for patients suffering from Hodgkin's disease or lymphosarcoma, albeit the effects were transient and the therapeutic window was narrow. These initial studies had already been performed during World War II, but as chemical warfare agents were the subject of investigation, they were regarded as classified information, which delayed publication until 1946. Publication of these results caused a wave of initial excitement, but the limited duration of treatment effects and the inability to ultimately cure cancer led to a change in mindset and to a widespread pessimism in the medical community. The resulting belief that cancer could be not cured by chemical agents lasted for many years. Still these hallmark results form the foundation of chemotherapy and led to the development of other alkylating agents like chlorambucil, melphalan, and cyclophosphamide (Figure 1.2), which are better tolerated and are still used today in clinical practice. It is noteworthy to correct a historical mistake that is frequently made. The bombing of a ship in Bari during World War II, which led to exposure of the crew to mustard gas, is often cited as the discovery of mustard's antitumor activity and the discovery of chemotherapy. This is not correct. Despite the fact that severe leucopenia was also observed in affected soldiers, the German air raid on the ships in the harbor of Bari took place on 2 December 1943, more than a year after patient J.D. had been treated. The development of chemotherapy is a fascinating topic, which has been reviewed in appropriate detail elsewhere [17].
Figure 1.2 S‐Lost, N‐Lost, modern agents.
1.3 Pregabalin
The discovery of pregabalin by Richard Silverman [18] and coworkers is a great example of successful identification of a small‐molecule drug in academia. γ‐Aminobutyric acid (GABA) was recognized early on as an important inhibitory neurotransmitter in the brain (Figure 1.3) [19]. The observation that GABA levels and L‐glutamic acid decarboxylase (GAD) activity is decreased in a number of pathologies like epilepsy, Alzheimer's, and Parkinson's disease has sparked the search for drugs to increase GABA levels in the brain. Pursued strategies include development of GABA receptor agonists, GABA uptake inhibitors, and inhibitors of 4‐aminobutyrate‐oxo‐glutarate aminotransferase. The latter enzyme is the key catabolic enzyme of GABA. Inhibitory effects of hydroxylamine on γ‐aminobutyric acid aminotransferase (GABA‐AT) were described already in 1961 [20]. In 1966, inhibition of (GABA‐AT) by aminooxyacetic acid was disclosed [21].
It was also demonstrated that inhibitors available at the time demonstrated insufficient selectivity [22]; consequently this approach was rendered as likely to be unsuitable to target epilepsy in humans. Shortly after starting his own laboratory at Northwestern University in Illinois in 1976, Silverman got interested in the biology of GABA‐AT and set out to develop chemical inhibitors. He published his first manuscript on the subject as early as 1980 [23]. While his first efforts relied on optimization of irreversible inhibitors, he was not able to overcome the intrinsic non‐specificity of these compounds. Specifically, inhibition of L‐glutamic acid decarboxylase (GAD) turned out to be an issue. GAD catalyzes the conversion of L‐glutamate, an excitatory neurotransmitter to the inhibitory neurotransmitter GABA. Inhibition of GAD would consequently lead to a decrease in GABA concentration and thus be highly undesirable.
In 1988 a visiting postdoc, Riszard Andruskiewicz from Gdansk University, joined Silverman's laboratory and was asked to work on synthesis and characterization of 3‐substituted GABA and glutamate analogues. He synthesized a set of 14 3‐alkyl‐GABA derivatives (Figure 1.4), 4‐methyl GABA, and the two enantiomers, as well as seven glutamate derivatives. Most interestingly and also somewhat surprisingly, all of the GABA analogues were found to be activators of L‐glutamic acid decarboxylase [24].
Figure 1.3 GABA biology.
Figure 1.4 3‐Me‐GABA analogues synthesized by Andruskiewicz and Silverman.
At that point (1989), they filed an invention disclosure and engaged in discussions with potential industrial partners, which led to start of collaborations with Upjohn Pharmaceuticals and Parke‐Davis Pharmaceuticals. The most potent compound, (R)‐3‐methyl‐GABA, did not display convincing anticonvulsant activity. Upjohn, concentrating on profiling the “best” compound, ended the cooperation at that point, while Parke‐Davis scientists tested all derivatives and found that the isobutyl derivative resulted in very favorable pharmacological effects. This was somewhat surprising, as the activation of GAD was significantly weaker for this compound compared with the corresponding methyl derivative (R/S)‐methyl‐GABA (239 % activity of GAD at a concentration of 2.5 mM versus 143 % activation for the racemic isobutyl analogue) [24]. However, after synthesizing the two isobutyl enantiomers, they could confirm that (S)‐3‐isobutyl‐GABA, later named pregabalin (Lyrica™), displayed one of the most pronounced anticonvulsant activities they ever tested. Several years later, Parke‐Davis scientists demonstrated that pregabalin binds to Ca2+‐channels, subsequently inducing calcium flux into the neuron. In turn this resulted in inhibition of glutamate and substance P secretion from excitatory neurons. So, in fact, the mechanism underlying the observed pharmacological effect of pregabalin, which was thought to be mediated by inhibition of GAD, was completely different. Inhibition of glutamate secretion does result in a similar pharmacological effect. Also the enhanced potency compared with other related derivatives could be explained by pregabalin being a substrate for the System L transporter, enabling active uptake into the brain [25]. Other compounds, like GABA itself, are not substrates of this transporter. Thus, their capability of crossing the blood–brain barrier is very limited.
Interestingly, in principle it only took the synthesis of 16 compounds to initiate the development of a successful drug candidate. Certainly many more compounds were produced and characterized in the Silverman laboratory, and still, the development of the actual drug required another 15 years until it was finally approved by the FDA in December 2004. But this drug development represents one of the rare cases where the final molecule was already obtained early on in the project. The originally assumed optimization rationale turned out to be not the correct one in various aspects, but by careful pharmacological examination, pregabalin was identified. This underlines the necessity to remain open to unexpected findings and keep the flexibility of adapting optimization goals and target values, or even the optimization strategy as a whole.
As a part of the deal with Silverman and the university, Pfizer (which had subsequently acquired both Park Davis and Upjohn), agreed to pay 4.5 % of global sales to the university, and Richard Silverman, who split his share with his coworker Andruszkiewicz, would receive 1.5 %. As Lyrica turned into a real blockbuster molecule, the university received an estimated US$ 1.4 billion in royalties.
On the topic of academic drug discovery, Silverman wrote in 2016: “Academic scientists are not constrained by the requirement of making products to remain viable; therefore, shortcuts are not necessary, and tangential observations can be explored, which may lead to new discoveries. Because of this, academic invention needs to be encouraged in all areas of pursuit to allow new products to become available to society; industry should assist in financing the development of these products.” [18]
1.4 Natural Product‐Derived Drug Discovery
Another important contribution of academia to drug discovery is providing specific expert knowledge on particular research areas and techniques. This knowledge, acquired within the academic group of a professor throughout his complete academic career, may represent the long‐sought solution to a specific problem that hampers progression of a compound to the market or prevents it from moving into clinical trials. This can be of particular value in the field of natural product research, as structural complexity is tremendous and compounds isolated from plants, bacteria, or marine organisms represent a rich source of potential drugs. However specific skills, e.g. in isolation, structure elucidation, and synthesis, can be required to identify the active compounds and make them accessible for further exploration.
The screening of natural products for bioactivities led to a multitude of starting points for chemical optimization to clinical candidates or even directly to live‐saving medications [26]. Several important examples discovered by academic groups are shown in Figure 1.5.
1.4.1 Antibiotics
Antibiotics figure prominently among the drugs discovered by academicians. Penicillin G represents one of the most influential findings in natural product research, saving the lives of millions of people. On 28 September 1928, Alexander Fleming, University of London, noted that on one of his bacterial culture dishes that was contaminated with a mold and that bacteria would die in proximity to the mold. He concluded that the mold produced an antibiotic substance. He published the results in 1929, [27] but the article and some following work did not receive much attention. The compound was difficult to isolate and it took until 1942 to reach the market [28]. Still today, penicillin G is on the WHO list of essential medicines, and in 1945, Fleming, together with Howard Florey and Ernst Boris Chain, received the Nobel Prize for medicine. Fleming also gave a beautiful description of his scientific finding, reminding us that chance is an essential part of scientific work – something scientists certainly cannot rely on, but should be prepared to spot and realize its potential.
One sometimes finds what one is not looking for. When I woke up just after dawn on September 28, 1928, I certainly didn't plan to revolutionize all medicine by discovering the world's first antibiotic, or bacteria killer. But I suppose that was exactly what I did [29].
Streptomycin is another compound listed on the WHO list of essential medicines. It was isolated for the first time by Albert Schatz, a PhD student in the laboratory of Selman A. Waksman at Rutgers University in 1943. The results were published on 1 January 1944 [30], and the compound was quickly progressed to the clinics. Waksman, who also discovered several other important antibiotic natural products, among them actinomycin and neomycin, received the unshared Nobel Prize for medicine in 1952 “for his discovery of streptomycin, the first antibiotic effective against tuberculosis.” However, it is highly debated, if the role of other contributors, in particular of Schatz, was downplayed [31].
Gramicidin S was discovered by Georgyi Frantsevitch Gause, a Russian microbiologist and his wife in 1942 [32]. By 1943 it was being used to treat wounded Soviet soldiers in World War II. Gramicidin S is produced by Brevibacillus brevis and consists of two identical fivemers, which are coupled to give a cyclic decapeptide.
Figure 1.5 Lead structures isolated from natural sources.
1.4.2 Anticancer Drugs
1.4.2.1 Camptothecin
In 1952, the National Advisory Cancer Council discussed the promise of chemotherapy for curing cancer and came to the conclusion that the available knowledge was not sufficient to support establishment of a specific funding program for drug discovery for cancer chemotherapy. However, in 1955, the Congress of the United States approved foundation of the Cancer Chemotherapy National Service Center (CCNSC) [33] and an associated budget of US$ 5 million for research on cancer. US$ 4.2 million were dedicated to grants supporting specific research proposals, while US$ 800 000 were reserved for acquisition and testing of new compounds. As a consequence, dedicated profiling laboratories were set up and a large compound collection was compiled. This effort was even strengthened in 1960, when the National Cancer Institute (NCI) partnered with the US Department of Agriculture (USDA) to collect plant and animal samples in search for natural products with potential anticancer activities. This alliance turned out to be very productive. Between 1960 and 1981, a total of 30 000 compounds was screened, and many pharmaceutically interesting structures were identified. At one of the involved profiling laboratories, the newly founded Research Triangle Park in North Carolina, chemists Monroe Elliot Wall and Mansukh C. Wani reported, among many others, the structure and activity of the natural product called camptothecin (Figure 1.6) [34].
Camptothecin, isolated from bark and stem of the Chinese Happy Tree (Camptotheca), was first chemically derived through total synthesis by Stork and Schultz [35] (Cornell University) in 1971, quickly followed by syntheses by the Danishefsky [36] (University of Pittsburgh) and Winterfeldt (University of Hanover) laboratories [37]. Camptothecin was identified as an inhibitor of topoisomerase I, acting through binding to the covalent topoisomerase‐DNA complex [38]. It is particularly toxic for cells in the S‐phase of mitosis. Albeit camptothecin itself proved too toxic to be used as a chemotherapeutic agent in patients, it served as a valuable lead structure for the approved drugs topotecan (Hycamtin™, approved in 1996 for treatment of ovarian cancer, in 2006 for cervical cancer, and 2007 for treatment of small‐cell lung carcinoma) and irinotecan (Camptosar™, a prodrug of topotecan approved in 1996 and used for treatment of colon cancer and small‐cell lung cancer) (Figure 1.6). Both derivatives are derived through semisynthesis.
Figure 1.6 Camptothecin and approved derivatives.
1.4.2.2 Taxol
The discovery of Taxol™ (paclitaxel, Figure 1.7) is another success story resulting from this campaign. In 1962, USDA botanist Arthur Barclay was on an excursion in Gifford Pinchot National Forest in Washington State to collect samples for the screening campaign. Among another 200 samples collected over the course of several months, he chose to take needles, twigs, and bark of the pacific yew. This turned out to be an important moment in cancer drug discovery.
Figure 1.7 Taxol derivatives.
Two years later, Wall and Wani at Research Triangle Park, North Carolina discovered a promising anti‐leukemic and tumor inhibitory activity of an extract made from the collected stem bark [39]. However, the isolated yield from the dried bark was only 0.02 %. They contacted USDA and requested more material to supply further studies. In September 1964, Barclay went back to Gifford Pinchot National Park and collected another 30 lb of bark.
The yew tree itself has long been known to possess toxic properties. Almost any part of the tree is toxic but the red cup around the seeds is particularly hazardous. The lethal dose of needles of the common yew is estimated to be about 50 g for an adult. The toxic effects are caused by the contained taxine alkaloids (mainly taxine B), leading to cardiogenic shock [40]. These cardiac effects are distinct from the primary mechanism of action of Taxol and can be attributed to binding to ion channels. The main component of this activity seems to be taxine B (Figure 1.7). Its structure is related to that of Taxol, but besides other differences, it lacks the oxetane ring and the benzoic amide and bears an exo‐methylene group and a dimethyl amino residue. However, cardiotoxic side effects are also reported for paclitaxel.
Taxol did display interesting activities against various cell models of cancer and was moderately active in different models of leukemia. However, its solubility in aqueous media is very low. The initial overall interest in the compound was low, also as its availability was very limited. This changed quickly after new in vivo models were introduced at NCI in the early 1970s, and Taxol was found to be strongly active in a mouse model of melanoma. The pharmacological activity finally led to its nomination as a development candidate in 1977, triggering further examination.
In the same year, Susan Band Horwitz (Albert Einstein College of Medicine, Yeshiva University) was contacted by the NCI and was asked to explore the effects of Taxol [41]. She performed some initial experiments and observed that Taxol was capable of stopping replication of HeLa cells even at nanomolar concentrations due to its ability to induce mitotic arrest. Furthermore, she discovered a completely new phenotype. Cells treated with Taxol would be filled with stable microtubule bundles. In later research, it was determined that Taxol efficiently stabilizes microtubules, thus arresting cell cycle [42]. This new mechanism created a tremendous interest in Taxol. However, access to the compound was very limited. In fact, the bark of an estimated 3000 trees is needed to allow isolation of 1 kg of Taxol. Given that the tree will inevitably die after its bark is harvested and the pacific yew is a slow‐growing species, the development process was slowed down significantly.
The intriguing complexity of the carbon backbone and its substitution pattern and the obvious need for alternative sources other than bark led to many academic groups pursuing synthetic approaches. Taxol's structure was elucidated by nuclear magnetic resonance (NMR) spectroscopy in 1971 by Wani [39], Holton [43], and Nicolaou [44] who reported the first two successful synthetic approaches to this challenging molecule, which may have marked a hallmark of natural product chemistry as this challenging molecule stimulated the whole field of natural product scientists. Other elegant syntheses were reported by Danishefsky [45], Wender [46], Kuwajima [47], Mukaiyama [48], and Takahashi [49], among others. However, the required complexity of the developed synthetic approaches limited their practical utility.
The first material for preclinical and clinical studies was still obtained from harvesting yew trees. Finally, in 1984 Taxol entered clinical phase 1 and phase 2 for ovarian cancer, which was initiated in 1985. Clinical profiling was delayed again by limited supply of the compound, but the first results were published by William McGuire (John Hopkins Center, New York) [50]. An initial response rate of 30 % was reported in women with cancer previously not responding to treatment. The increasing compound demands made further clinical profiling almost impossible. In addition, concerns about the environmental impact sparked public debate [51]. Specifically, it was discussed if it was appropriate to risk extinction of species to support clinical trials, which, if eventually successful, could potentially save some individuals. In 1987, NCI estimated that 60 000 lb of bark would have to be collected to support the requests for phase 2 studies, with another 60 000 lb required in 1989.
Previously, 6500 lb of bark had sufficed for supporting research for 10 years and only 2000 lb of bark were needed to provide the required amounts of Taxol from the period 1962 to 1966. In 1989, 27 years after its discovery, no suitable route to access larger compounds quantities was within reach, and no patents protecting the compound were issued. The NCI decided to transfer the project to a pharmaceutical company for resolution of the remaining development issues and commercialization. At this time not too many companies were interested in cancer chemotherapy, as research costs were high and the expected chances of actually developing an effective drug were regarded as very small. Furthermore, in 1988 chemotherapy accounted for less than 3 % of the global drug market, compared with more than 17 % for cardiovascular drugs. Consequently, only four companies applied. The NCI finally decided to transfer rights to development under a cooperative research and development agreement to Bristol Meyers Squibb (BMS) in 1991. The contractual terms, which were granted to BMS, were very favorable; BMS received not only a market exclusivity for (the non‐patented) Taxol but also an orphan drug status, the right to use all NCI‐derived clinical data for applying for additional indications beyond ovarian cancer and, in a separate agreement with the Bureau of Land Management and the Forest Service, the right of first refusal on all products obtained from yew trees grown on public land [52]. This exclusivity spurred a public debate on granting a monopoly for plants on public land to a private enterprise and for giving exclusivity for a new cancer treatment based on data obtained by public funding. Also, concerns rose that yew trees could be harvested to the point of species extinction, as a result, the Pacific Yew Act was passed in 1992, which regulated yew harvesting to ensure careful management of remaining pacific yew resources and to provide sufficient supply of Taxol in the future. In 1992, BMS secured the name “Taxol” as a trademark – despite its utilization for more than 20 years – and created the new generic name “paclitaxel” for the drug.
The shortcomings of compound supply were finally resolved by combining results from different academic laboratories. Greene, Potier, and coworkers discovered that needles of the English Yew (Taxus baccata) contained large amounts (up to 0.1 %) of 10‐deacetyl baccatin III. They developed a method to selectively silylate the hydroxyl group at C‐7, followed by acetylation of the hydroxyl group at C‐10 with enantiomerically pure results (Figure 1.8) [53]. Holton at Florida State University developed an effective β‐lactam opening procedure. As he filed patent applications on this process, licensing by BMS, resulted in royalty payments of more than US$ 400 million to Florida State University.
Today, Taxol is a widely examined cancer treatment, with a total of 3875 studies on paclitaxel listed on clinicaltrials.gov on 1 March 2020. It is approved in the United States for the treatment of breast, pancreatic, ovarian, Kaposi's sarcoma, and non‐small‐cell lung cancers.
One limitation of Taxol is its very poor aqueous solubility of less than 0.01 mg/mL. The used formulation for clinical use as an intravenous injection is composed of a 1 : 1 mixture of cremophor EL (polyethoxylated castor oil) and ethanol, diluted with dextrose solutions or brine [54]. Cremophor, however, is not regarded as an ideal vehicle for human use, as it can create hypersensitivity, alter endothelial and cardiac muscle function and induce several other side effects. Furthermore, the concentration of cremophor that has to be used is unusually high.
Figure 1.8 Semisynthetic approaches to Taxol.
Source: Based on Denis et al. [53].
Neil Desai, a chemical engineer, and Patrick Soon‐Shiong, surgeon and entrepreneur, met at a NCI organized conference on Taxol in 1992 and reasoned that it should be possible to derive a formulation, which was be better tolerated after application. After an intense optimization effort, they discovered that paclitaxel bound to albumin and formulated as nanoparticles can be a safer alternative which significantly improves the handling, solubility, and side effect profile of Taxol.
The compound, termed Abraxane™, could be dosed providing about 50 % higher paclitaxel amounts and still displayed better tolerability. Clinical studies reported improved response rates accompanied with improved tolerability [55]. This kind of innovation can be rather seen as an incremental one, but the specific approach can help utilizing the full potential of a given treatment. Abraxis, the company that was founded to drive the development of the reformulation platform and specifically Abraxane, was sold to Celgene in 2010 for US$ 2.9 billion.
Paclitaxel represents a perfect example for the impact of different contributions from individual researchers on the overall success of a drug. Here, isolation, structure elucidation, structure–activity relationship (SAR), access routes, and galenic aspects were tackled by a large number of scientists, contributing their specific experience and being able to make paclitaxel an important treatment option for various cancers.
1.4.2.3 Epothilones
A related example is the work on epothilones (Figure 1.9). Initially isolated from the myxobacterium Sorangium cellulosum by Hofle et al. [56] in the German Federal Research Center Gesellschaft für Biotechnologische Forschung (GBF) in Braunschweig, the macrolides raised attention due to their structural and biological properties.
Figure 1.9 Epothilone derivatives.
The formation of the 16‐membered, highly functionalized ring system stimulated the creativity of many academic groups and spurred the development of new and effective synthetic methods, e.g. ring closing metathesis for creation of the epothilone ring system. Among many others, the total syntheses reported by renowned academic experts such as Samuel Danishefsky [57], K.C. Nicolaou [58], Alois Fürstner [59], Dieter Schinzer [60], Eric Carreira [61], and Johann Mulzer [62] are particularly noteworthy, displaying a wide range of different approaches. Several companies, encouraged by synthetic accessibility of the core structures, got engaged in lead optimization programs. To date one derivative, ixabepilone (Figure 1.9), is used as a medication to treat advanced or metastatic breast cancer. It was developed by BMS [63] and received FDA approval in 2007.
1.4.2.4 Eribulin
While total synthesis was shown not to be a feasible production route for epothilone and Taxol derivatives, the approach still proved to be key for the development of another microtubule stabilizing agent. In 1986, Hirata and Uemura described the isolation of several family members of a novel class of natural products from the marine sponge Halichondria okadai [64]. This class, named halichondrins, consists of several family members that vary in their oxidation state. They show a remarkable structural complexity. Halichondrin B (Figure 1.10) possesses a staggering 32 stereocenters. In particular halichondrin B displayed outstanding cytotoxicity against a panel of 60 human cancer cell lines, which at that time was newly established at the NCI and became known as the NCI‐60. Even more importantly, it showed excellent activity in in vivo cancer models. However, while it could be also detected in a few sponges of the Axinella, Phakellia, and Lissodendoryx families, its availability was extremely limited, as it could only be obtained in minimal quantities from the harvested sponges. Owing to the high potency of the compound, calculations indicated that only 10 g should be sufficient to supply clinical development and future need for commercialization was estimated to be between 1 and 5 kg. However, the producer organisms are rare, and it was calculated that at the time the available world supply of halichondrin B derived through extraction of one ton of harvested Lissodendoryx n. sp. 1 would amount to only 300 mg. Lissodendoryx n. sp. 1 is only found in an area of about 5 km2 at a depth of 80 to 100 m, south of the coast of New Zealand. Calculations performed in 1993 estimated the total available biomass of Lissodendoryx to be only (289 ± 90) tons [65]. Yoshoito Kishi from Harvard University became interested in the unique structure of halichondrin B and set out to develop a synthetic access route. His main motivation was actually not in the anticancer properties of the drug, but at demonstrating the utility of the Nozaki–Hiyama–Kishi reaction in complex real‐world examples. This was a grand challenge, but in 1992, Kishi and his coworkers succeeded in completing the first synthesis, which comprised a total of 128 steps [66]. Also in 1992, the NCI nominated halichondrin B for preclinical testing. Eisai decided to license the synthesis of halichondrin B patented by the Kishi laboratory and initiated a very unique and fruitful collaboration in which researchers at Eisai were supplied with advanced intermediates by the Kishi laboratory. This joint effort led to establishment of several analogues and the understanding of the scaffold's SAR. In the course of this exploration, the anticancer activity of halichondrin B could be associated with the right‐hand side of the molecule, allowing a significant simplification of the molecule and finally resulting in the identification of E7389, later termed eribulin (Figure 1.10). The SAR studies and associated synthetic challenges have been reviewed in detail [67]. Compound availability by total synthesis was essential to start clinical work. Preclinical data for eribulin were more than convincing, but for internal reasons Eisai could not pursue the compound at the time, so it was decided to explore the compound's effects through a NCI‐sponsored phase 1 clinical trial. The first results were positive, so Eisai decided to sponsor further trials [68]. The compound received FDA approval in November 2010, only eight months after submission of the application. Today it is available in 50 countries for treatment of advanced metastatic breast cancer. It is the first drug that has shown improvement of survival in women with heavily pretreated metastatic breast cancer.
Figure 1.10 Structures of halichondrin B, eribulin mesylate, and E7130.
Albeit structurally significantly simplified, eribulin still bears 19 stereogenic centers and represents a showcase for organic synthesis, enabling access to structural complexity. Thorough optimization by the Kishi group [69] and by the Eisai process development group [70] led to significant improvement of the synthesis. Eribulin is now accessible in a 62‐step synthesis and still represents the most complicated technical synthesis of a marketed drug to date. This record may be in danger, though, as the Kishi group recently reported the synthesis of an even more complex development candidate, termed E7130 (Figure 1.10). While the initial synthesis took a total of 109 steps, they managed to improve the syntheses to “only” 92 – significantly higher yielding – steps and obtained remarkable 11 g of material [71]. E7130 is now undergoing clinical trials and may eventually become a successor to eribulin.
1.4.3 Artemisinin and Artemether
An illustrative alternative example for the application of expert knowledge to tackle a roadblocking problem is the flow synthesis of artemisinin (Figure 1.11), developed by Peter Seeberger and coworker [72]. The discovery of artemisinin is a thrilling story of its own, which has been reviewed several times [73
