Progress in Medicinal Chemistry

1st Edition, Volume 63 - October 4, 2024
Editors: Jonathan Bentley, Tilly Bingham
Language: English
Hardback ISBN:
9 7 8 - 0 - 4 4 3 - 2 9 7 8 0 - 9
eBook ISBN:
9 7 8 - 0 - 4 4 3 - 2 9 7 8 1 - 6

Progress in Medicinal Chemistry, Volume 63 highlights new advances in the field, with this new volume presenting interesting chapters written by an international board of author… Read more

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Progress in Medicinal Chemistry, Volume 63 highlights new advances in the field, with this new volume presenting interesting chapters written by an international board of authors. Specific chapters in this release include Harnessing conformational drivers in drug design, Recent Advances in the Medicinal Chemistry of Heterobifunctional Derivatives for Protein Homeostasis, and A Decade of Antimalarial Drug Discovery: New Targets, Tools and Molecules.

Progress in Medicinal Chemistry, 63
Cover image
Title page
Table of Contents
Copyright
Contributors
Preface
Reference
Chapter One Harnessing conformational drivers in drug design
Abstract
Keywords
1 Introduction
2 Steric clashes
2.1 Torsional strain
2.2 Impact of substitution on the conformation of the cyclohexane ring
2.3 Allylic strain
2.4 Syn-pentane
3 Lone pair-lone pair repulsion
4 Dipole-dipole interaction
5 CH-π interaction
6 π-π Interaction
7 Conjugation
7.1 Biaryls
8 Intramolecular hydrogen bond (IMHB)
9 Gauche effect
10 Anomeric effect
11 n to σ-hole
12 n to π* interaction
13 NMR spectroscopy as an invaluable tool in drug design
13.1 NMR case studies
14 Conclusions
Acknowledgements
References
Chapter Two To homeostasis and beyond! Recent advances in the medicinal chemistry of heterobifunctional derivatives
Abstract
Keywords
Introduction
1 Recent advances in the medicinal chemistry of heterobifunctional degraders
1.1 First to clinic—The discovery of ARV-110 and ARV-776
1.2 Delivering improved DMPK through linkerology—The discovery of CFT8634
1.3 Delivering degraders for non-oncology indications—The discovery of the IRAK4 degrader KT-474
1.4 Improving physicochemical properties through E3 recruiter warhead modification
1.5 Delivering selective target engagement through heterobifunctional degraders
2 Recent advances in the screening of heterobifunctional degraders
2.1 Approaches to screening degraders
2.2 Direct to biology (D2B) approaches
3 Extending the repertoire of E3 ligases
4 Heterobifunctional degraders beyond E3 ligase recruiters
4.1 Degradation via localisation to chaperone proteins (CHAMPs)
4.2 Degradation of mitochondria via specific localisation of the ULK1 kinase
4.3 Degradation via direct proteasomal recruitment—Targeting RPN11
4.4 Inducing protein stability—DUBTACs
4.5 Altering post-translational modifications—AceTACs
4.6 Deactivation proteins through sequestration—RIPTACs
4.7 Selective sub-cellular localisation—TRAMs
5 Advances in our understanding of heterobifunctional degrader DMPK
5.1 Factors important to achieving good oral exposure
5.2 Physicochemical property space
5.3 In vivo pharmacokinetic studies
5.4 Additional DMPK considerations
6 Advances in the scale-up of heterobifunctional degraders for clinical supply—Challenges and solutions
7 Heterobunctional bifunctional degraders in the clinic
Summary and outlook
Acknowledgements
References
Chapter Three Another decade of antimalarial drug discovery: New targets, tools and molecules
Abstract
Keywords
1 Introduction
2 The need for new drug targets; new tools for target validation
2.1 Phenotypic vs target-driven approaches
2.2 The Malaria Drug Accelerator (MalDA)
2.3 Target validation in malaria drug discovery
2.4 The NOD scid gamma (NSG) humanized mouse efficacy model
2.5 Advances in predictive modelling and the advent of open-source software
3 Non-kinase drug targets
3.1 ATPase4 (ATP4)
3.2 Targeting protein translation in Plasmodium parasites
3.3 Acetyl-CoA synthetase (AcAS)
3.4 Farnesyl diphosphate synthase/geranylgeranyl diphosphate synthase (FPPS/GGPPS)
4 Kinases as targets for malaria
4.1 Relevant kinases in current malaria drug discovery
4.2 Other Plasmodium kinases and their inhibitors
5 Future directions and conclusion
References

Jonathan Bentley

Jonathan Bentley is a VP, Scientific Director at Evotec in the Discovery Chemistry department in Abingdon UK. He is responsible for the scientific strategy on multiple collaborations and provides strategic leadership and support for scientific delivery across multi-disciplinary drug discovery programs. Within Evotec, he leads the cross-functional global Design Evolution initiative. He joined Evotec as a Project Leader in 2007 and was promoted to VP in 2020. Prior to Evotec, he was a Research Leader at the Psychiatry Centre of Excellence in Drug Design for GSK, Verona for 3.5 years after spending the formative phase of his industrial career at Vernalis in Reading, UK for 7 years. He has contributed to the identification of multiple clinical and preclinical candidates as project leader, or as part of multidisciplinary drug discovery teams in collaboration with international scientific and strategic partners. He has a PhD in Synthetic Organic Chemistry from the University of Bristol, sponsored by SmithKline Beecham (1995). He spent a year in a post-doctoral position at University of Cape Town, supported by Schering AG (1995-6). He has worked on projects across many different therapeutic areas including Oncology, Inflammation, Pain, CNS (Anxiety, Depression, Drug Dependence, Schizophrenia, Insomnia, Neurodegeneration), Metabolic Diseases and Women‘s Health. He has enjoyed working on multiple target classes including agonists, antagonists, PAMs and NAMs of GPCRs from all classes, diverse enzyme inhibitors and activators, and ion channel blockers, openers, and modulators, as well as phenotypic endpoints. He was the first recipient of the RSC / SCI Capps-Green-Zomaya award in 2004.

Affiliations and expertise

VP, Scientific Director, Evotec, Discovery Chemistry Department, Abingdon, UK

Tilly Bingham

Tilly (Matilda) Bingham is a drug discoverer with over 20 years’ experience of working in the pharmaceutical R&D sector in ‘large pharma’ (Organon, Schering-Plough, MSD), Biotech (Redx Pharma), CRO (Concept Life Sciences) and is currently Executive in Residence at Cumulus Oncology. Tilly’s early career was spent working as a medicinal chemist in CNS therapeutic areas where her research focussed on design strategies for getting small molecule therapeutics across the blood brain barrier for targets including the GPCRs OX2R, V1R and CGRP. Then, as Head of Research and Operations at Redx Pharma she oversaw the discovery and development of oncology and fibrosis clinical candidates, including the clinical candidate porcupine inhibitors RXC004 (oncology), RXC006 (AZD5055, fibrosis), Pan RAF inhibitor (JZP815) and FDA approved BTK inhibitor Pirtobrutinib. As VP Science and Chief Scientific Officer at the UK CRO Concept Life Sciences she oversaw multiple research programmes and the development of new research capability across the group. In her current role as Executive in Residence at Cumulus Oncology Tilly is employing her significant expertise in pre-clinical drug discovery to accelerate oncology innovation to key value inflection points.

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