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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5979_Библиотеки_им_академика_М_И_Перельмана
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Surya K. De
Drug Design
and Discovery
Inhibitors of Mitogen-Activated Protein
Kinases
Drug Design and Discovery
SuryaK.De
Drug Design and Discovery
Inhibitors ofMitogen-Activated Protein
Kinases
ISBN 978-3-031-75681-8 ISBN 978-3-031-75682-5 (eBook)
https://doi.org/10.1007/978-3-031-75682-5
© The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature
Switzerland AG 2024
This work is subject to copyright. All rights are solely and exclusively licensed by the Publisher, whether
the whole or part of the material is concerned, specically the rights of translation, reprinting, reuse of
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The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication
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The publisher, the authors and the editors are safe to assume that the advice and information in this book
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If disposing of this product, please recycle the paper.
SuryaK.De
Conju-Probe
San Diego, CA, USA
v
Preface
After proteases, the protein kinase family is the second largest enzyme family and
the fth largest gene family in humans. Protein kinases are the second largest group
of drug targets after G-protein coupled receptors (GPCR) and they account for
almost 20–30% drug development pipelines. The human genome has almost 518
kinase genes and 106 pseudogenes. Protein kinases comprise 2% of the mammalian
genome and catalyze the transfer of the γ-phosphoryl group of the ATP to specic
protein substrates. This covalent post-translational modication is a crucial compo-
nent of normal cellular communication and maintenance of homeostasis. The sig-
nals can initiate inside or outside the cells and pass through a series of steps with
multiple enzymes and messengers. The MAPK family comprises three major groups
such as ERKs, JNKs, and p-38.
Each chapter embedded in this book covers important information regarding dif-
ferent approaches in designing small molecules for MAP kinase inhibitors. There
are four strategies utilized by different groups in developing MAP kinase inhibitors
such as ATP site inhibitor, non-ATP site inhibitor, bi-dentate inhibitor, and covalent
inhibitor. The verication of the ability of small molecules or small peptides to
modulate MAPK activity as a diabetes, cancer, and Parkinson disease or as a diag-
nostic and /or prognostic tool is now possible and probable. The medicinal chemists
could use these factors in laying out new strategies for developing novel MAPK
inhibitors. Nevertheless, multiple approaches to identify MAPK inhibitors with
higher selectivity and safety windows may lead to more efcient and faster thera-
pies in the years to come. We anticipate that more studies describing MAPK func-
tions in human health make this eld more attractive and will continue to be of
substantial intrinsic merit. This book offers the principles of drug design and suc-
cessful implementation of MAP kinase inhibitors from hit, and latest development
in this eld.
San Diego, CA, USA SuryaK.De
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vii
Contents
1 An Overview of Protein Kinase Inhibitors . . . . . . . . . . . . . . . . . . . . . . 1
1.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
1.1.1 Classication of Kinases . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
1.1.2 Protein Kinase Domains . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
1.1.3 Types of Kinase Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . 24
1.1.4 FDA-Approved Kinase Inhibitors . . . . . . . . . . . . . . . . . . . . 25
1.1.5 Chemical Structure of FDA-Approved Kinase Inhibitors . . 25
1.1.6 MAP Kinases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
2 Biological Roles of MAP Kinases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
2.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
2.2 MAPK Pathway: The Basics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44
2.3 Role of MAP Kinases 8, 9, 10 in Neurodegenerative Diseases . . . . 46
2.4 Role of MAP Kinases 8, 9, 10 in Obesity and Type-2 Diabetes . . . 46
2.5 Role of MAP Kinases 8, 9, 10 in Rheumatoid Arthritis . . . . . . . . . 47
2.6 Role of MAP Kinases 8, 9, 10 in Bronchial Asthma . . . . . . . . . . . . 47
2.7 Role of MAP Kinases 8, 9, 10 in Oncology . . . . . . . . . . . . . . . . . . 48
2.8 Structures of MAPK 8, 9, 10 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49
2.9 Interactions of MAPK8, 9, 10 with Other Proteins . . . . . . . . . . . . . 50
2.10 Localization of MAP Kinases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52
2.11 Landmark of MAP Kinases 8, 9, 10 . . . . . . . . . . . . . . . . . . . . . . . . 53
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54
3 ATP-Competitive Inhibitors of MAP Kinases . . . . . . . . . . . . . . . . . . . 67
3.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67
3.2 ATP-Competitive Inhibitors of JNK . . . . . . . . . . . . . . . . . . . . . . . . 68
3.2.1 Inhibitors from Serono . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68
3.3 Inhibitors from Eisai . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69
3.4 Inhibitors from Pzer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70
3.5 Inhibitors from Abbott Lab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70
3.6 Inhibitors from Elan Pharmaceuticals . . . . . . . . . . . . . . . . . . . . . . . 73
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3.7 Inhibitors from Roche . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76
3.8 Inhibitors from Takeda . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77
3.9 Inhibitors from AstraZeneca . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80
3.10 Inhibitors from Vertex . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81
3.11 Inhibitors from GSK . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82
3.12 Inhibitors from Union Chimique Belge (UCB) . . . . . . . . . . . . . . . . 82
3.13 Inhibitors from Universität Tübingen . . . . . . . . . . . . . . . . . . . . . . . 84
3.14 Inhibitors from Scripps Research Institute . . . . . . . . . . . . . . . . . . . 86
3.15 Inhibitors from Hanyang University . . . . . . . . . . . . . . . . . . . . . . . . 90
3.16 Inhibitors from Celgene (Now BMS) . . . . . . . . . . . . . . . . . . . . . . . 91
3.17 Inhibitors from CHDI Foundation . . . . . . . . . . . . . . . . . . . . . . . . . . 93
3.18 Inhibitors from Peking University . . . . . . . . . . . . . . . . . . . . . . . . . . 93
3.19 Inhibitors from Montana State University . . . . . . . . . . . . . . . . . . . . 94
3.20 Inhibitors from Nanjing Tech University . . . . . . . . . . . . . . . . . . . . . 94
3.21 Inhibitors from Sichuan University . . . . . . . . . . . . . . . . . . . . . . . . . 95
3.22 Development of New Clinical Candidate CC-90001
as a JNK Inhibitor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96
3.23 ATP-Competitive ERK1/2 Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . 98
3.24 Development of Clinical Candidates as ERK1/2 Inhibitors . . . . . . 104
3.25 Development of Clinical Candidates as p38 MAPK Inhibitors . . . . 110
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120
4 Non-ATP Site Inhibitors and Bi-dentate Inhibitors . . . . . . . . . . . . . . . 135
4.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135
4.2 Small Peptides as ATP-Noncompetitive Inhibitors
of MAPK 8, 9, 10 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 136
4.3 Small Molecules as ATP-Noncompetitive JNK
(MAPK 8, 9, 10) Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139
4.4 Dual Site Binding MAP Kinase 8, 9, 10 Inhibitors . . . . . . . . . . . . . 142
4.5 Bi-dentate Inhibitors of MAP Kinase 8, 9, 10 . . . . . . . . . . . . . . . . . 144
4.6 Small Molecule Bi-dentate Inhibitors of MAK Kinase 8, 9, 10 . . . 148
4.7 Allosteric Inhibitors of ERK1/2 (Non-ATP-Competitive ERK
Inhibitors) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149
4.8 Allosteric Inhibitors of p38 MAPK . . . . . . . . . . . . . . . . . . . . . . . . . 151
4.9 Development of Clinical Candidate BIRB-796 as an Allosteric
p38 MAP Kinase Inhibitor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154
5 Covalent Inhibitors of MAP Kinases . . . . . . . . . . . . . . . . . . . . . . . . . . 159
5.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159
5.2 Ritlecitinib . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 160
5.3 Dimethyl Fumarate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 160
5.4 Wortmannin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 160
5.5 Afatinib . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161
5.6 Ibrutinib . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161
5.7 Bortezomib . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161
Contents
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5.8 Irreversible Covalent Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . 162
5.9 Reversible Covalent Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 164
5.10 Irreversible Covalent Binding Warheads . . . . . . . . . . . . . . . . . . . . . 165
5.11 Reversible Covalent Binding Warheads . . . . . . . . . . . . . . . . . . . . . . 166
5.12 Representative Targeted Covalent Inhibitors and Their Target
and Indication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 169
5.13 Covalent Inhibitors of MAPK 8, 9, 10 (JNKs) . . . . . . . . . . . . . . . . 169
5.13.1 Covalent Inhibitors of ERK1, 2 . . . . . . . . . . . . . . . . . . . . . . 173
5.13.2 Fragment-Based Discovery of Covalent ERK1/2
Inhibitor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 175
5.13.3 Covalent ERK1/2 Inhibitor Targeting Outside
of ATP Binding Site . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 175
5.14 Covalent Inhibitors of p38 MAP Kinases . . . . . . . . . . . . . . . . . . . . 179
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 183
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191
Contents
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xi
About the Author
Surya K. De is a Director at Conju-Probe, San Diego, California, USA. Surya
K. De obtained his Ph.D. in Organic Chemistry from Jadavpur University, Kolkata
(Calcutta), India. He worked at the University of Washington (Seattle), Purdue
University (West Lafayette, Indiana), the Scripps Research Institute, and Sanford-
Burnham Medical Discovery Institute prior to joining a biotech company. He has
published over 120 papers in reputed international journals, covering a broad array
of specialized topics in science, and he holds 15 US and international patents. He
has published four solo-authored books. He has been a fellow of the Royal Society
of Chemistry (London, UK), the Royal Society of Medicine (London, UK), the
American Institute of Chemists (USA), and the Indian Chemical Society. He was a
recipient of P. R. Vijayalaxmi Award for Innovation in Cancer Research (2023,
USA). He has been an elected councilor at the American Chemical Society
since 2022.
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xiii
Common Abbreviations and Acronyms
AA Anaplastic anemia
ABC Advanced breast cancer
ACE Angiotensin converting enzyme
ABMT Autologous bone marrow transplant
AD Alzheimer’s disease
ADR Adverse drug reaction
ADP Adenosine diphosphate
AFP Alpha-fetoprotein
AKT AKR mouse thymoma kinase
ALBL Acute lymphoblastic B-cell leukemia
ALAT Alanine aminotransferase
ALCL Anaplastic large-cell lymphoma
ALK Anaplastic lymphoma kinase
AML Acute myeloid leukemia
ALL Acute lymphoblastic leukemia
ALT Alanine aminotransferase
AMKL Acute megakaryocytic leukemia
AMP Adenosine monophosphate
APDS Activated PI3K delta syndrome
AP-1 Activator protein 1
ATP Adenosine triphosphate
BBB Blood-brain barrier
BCC Basal cell carcinoma
BPDCN Blastic plasmacytoid dendritic cell neoplasm
Bcl2 B-cell lymphoma 2
BMI Body mass index
BMX BMX nonreceptor tyrosine kinase
BTK Bruton’s tyrosine kinase
BRCA1 Breast cancer gene 1
BRCA2 Breast cancer gene-2
BRAF v-raf murine sarcoma viral oncogene homolog B1
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