Drug Discovery Stories

From Bench to Bedside

1st Edition - October 18, 2024
Editors: Bin Yu, Peng Zhan
Language: English
Paperback ISBN:
9 7 8 - 0 - 4 4 3 - 2 3 9 3 2 - 8
eBook ISBN:
9 7 8 - 0 - 4 4 3 - 2 3 9 3 3 - 5

Drug Discovery Stories: From Bench to Bedside presents a collection of cases on the development of highly successful pharmaceuticals. It delves into the realm of drug discovery… Read more

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Drug Discovery Stories: From Bench to Bedside presents a collection of cases on the development of highly successful pharmaceuticals. It delves into the realm of drug discovery, exploring the structural biology and biological functions of the sought-after targets. The book covers the identification of promising compounds, their transformation from hits to leads through meticulous optimization, and the elucidation of how key compounds interact with the target (in essence, providing invaluable insights for drug design). Additionally, it covers essential information such as the pivotal biological and PK data of lead compounds, any noteworthy clinical results, and a comprehensive overview of other candidate compounds.

The field of drug discovery and development has experienced rapid evolution, with numerous new drugs receiving approval each year. While several books have been published on this subject, there is a pressing need for a new book series that accurately reflects the current advancements in drug discovery. This book aims to not only cater to the drug discovery community but also engage other communities involved in chemical biology, synthetic chemistry, and pharmacology.

Title of Book
Cover image
Title page
Table of Contents
Copyright
Dedication
List of contributors
About the editors
Foreword 1
Foreword 2
1 The genesis of drug discovery stories
2 Analyzing blockbuster drugs: a kaleidoscope of success
3 Newly approved drugs: pioneering the future of medicine
4 Key aspects of drug development: navigating the odyssey
5 Diversity in voices: a global mosaic of contributors
6 Embarking on a collective exploration
Section 1: Drug discovery techniques and strategies
Chapter 1. Artificial intelligence in early stages of structure-based drug discovery
Abstract
1.1 Introduction
1.2 Target structure determination
1.3 Binding site elucidation
1.4 Chemical libraries
1.5 Structure-based virtual screening
1.6 Conclusions
Acknowledgments
References
Chapter 2. Target-based vs phenotypic drug discovery: opportunities and challenges with evidence-based application
Abstract
Graphical abstract
2.1 Introduction
2.2 Phenotypic drug discovery
2.3 Opportunities and challenges in phenotypic drug discovery
2.4 Use of artificial intelligence to improve phenotypic drug discovery
2.5 Modern phenotypic drug discovery advancements
2.6 Target-based drug discovery
2.7 Target identification and validation
2.8 Challenges of target-based drug discovery
2.9 Conclusion and future perspectives
References
Chapter 3. Hit discovery from DNA-encoded chemical library
Abstract
3.1 Principles of DNA-encoded chemical library
3.2 Introduction to encoding methods, DNA-compatible reactions, selection methods, and sequencing analysis
3.3 Case studies and summary
3.4 Summary and outlook of DNA-encoded chemical library in drug discovery
References
Chapter 4. Discovery of lead compounds from pseudo-natural macrocycles enabled by modular biomimetic strategy
Abstract
4.1 Introduction
4.2 Method and proof of concept
4.3 Future perspectives and conclusion
References
Chapter 5. Macrocyclization strategy in kinase drug discovery
Abstract
5.1 Introduction
5.2 Advantages of macrocyclization
5.3 Computational design strategy
5.4 Conclusion and perspectives
References
Chapter 6. Cobalt-catalyzed C–H functionalization for the synthesis of chiral heterocyclic molecules
Abstract
6.1 Introduction
6.2 Conclusions
Acknowledgments
References
Chapter 7. Advancing proteolysis targeting chimeras toward clinical drug developments
Abstract
7.1 Introduction
7.2 Proteolysis targeting chimeras in clinical developments
7.3 Conclusions and outlooks
Acknowledgments
References
Chapter 8. A future battle, small-molecule drugs for cancer stem cell targeted therapy
Abstract
8.1 Introduction
8.2 Key signaling pathways in cancer stem cells
8.3 Key cancer stem cell markers and relating anticancer drugs
8.4 Existing problems and future perspective
8.5 New thoughts for targeting cancer stem cells
8.6 Conclusion
Acknowledgments
Declaration of interests
Author contributions
References
Chapter 9. Stem cell therapies for combating emerging and reemerging viral infections
Abstract
9.1 Introduction
9.2 Emerging and reemerging viral infections all over the world
9.3 Therapeutic achievements of stem cell therapy
9.4 Role of mesenchymal stem cells (MSCs) to prevent emerging and reemerging zoonotic viral infections
9.5 Stem cell therapy for the treatment and prevention of viral diseases
9.6 Stem cell therapy: a possible treatment for influenza and coronavirus-induced acute lung damage
9.7 T-cell therapy helps overcome stem cell transplant viral infections
9.8 Molecular mechanisms responsible for mesenchymal stem cell–based (MSCs) treatment of viral diseases
9.9 Clinical studies for Coronavirus disease 2019 stem cell therapy
9.10 Challenges and opportunities for MSC-based therapies in viral infections
9.11 Conclusion and future perspectives
References
Chapter 10. Targeting autophagy with pharmacological small molecules to treat human diseases
Abstract
10.1 Introduction
10.2 Autophagy and human diseases
10.3 Discovery of pharmacological small molecules targeting autophagy
10.4 Discovery of pharmacological small molecules based on autophagic degradation strategies
10.5 Conclusions and perspectives
Acknowledgments
References
Chapter 11. Interferons in human papillomavirus infection: antiviral effectors or immunopathogenic role?
Abstract
11.1 Introduction
11.2 Human papillomavirus
11.3 Current and future directions in the treatment of human papillomavirus-related diseases
11.4 The interferon response
11.5 In vitro studies of the innate antiviral signaling pathways to human papillomavirus
11.6 In vivo studies of the innate antiviral response to human papillomavirus
11.7 Interferon as an antiviral drug for the treatment of human papillomavirus infection
11.8 Conclusion
References
Chapter 12. Selenium and small molecules: a symbiotic partnership
Abstract
12.1 Introduction
12.2 One case study: ebselen
12.3 Conclusion
Acknowledgments
References
Chapter 13. Novel combinations of CD33-targeted immunotherapies
Abstract
13.1 CD33-targeted immunotherapies
13.2 Bridge to transplantation
13.3 Combination with small molecule
13.4 Novel combinations of CD33-targeted therapies
13.5 Conclusions
Acknowledgments
References
Chapter 14. Novel payloads of antibody-drug conjugates
Abstract
14.1 Background
14.2 proteolysis-targeting chimeras-based antibody–drug conjugate payloads
14.3 Dual-payload antibody–drug conjugates
14.4 Immune antibody–drug conjugate payloads
14.5 Other potential antibody-drug conjugate payloads
14.6 Conclusions and perspectives
References
Chapter 15. Antibody−drug conjugates: a new generation of cancer vaccines
Abstract
15.1 Introduction
15.2 Development and generation of antibody drug conjugates
15.3 Structure and mechanism of antibody−drug conjugate
15.4 Discovery and drug design of antibody−drug conjugate
15.5 Challenges and limitations in clinical use
15.6 Clinical applications and efficacy
15.7 Next-generation antibody−drug conjugates
15.8 Concluding remarks and future directions
References
Chapter 16. mRNA vaccines: the next frontier in disease prevention
Abstract
16.1 Introduction
16.2 The mRNA revolution
16.3 Conclusion and future directions
References
Chapter 17. Unravelling the drying techniques of protein biopharmaceuticals
Abstract
17.1 Introduction
17.2 Biopharmaceutical products
17.3 Proteins—structure and configuration
17.4 Instability of protein-based biopharmaceutical products
17.5 Drying techniques for protein-based biopharmaceutical products
17.6 Stabilizers for protein-based biopharmaceutical products
17.7 Conclusion
Acknowledgments
References
Section 2: Drug discovery case studies
Chapter 18. Lenacapavir: a first-in-class HIV-1 capsid inhibitor for the treatment of multidrug-resistant HIV infections
Abstract
18.1 Introduction
18.2 The discovery of HIV CA modulator LEN
18.3 Mechanism of action of HIV CA modulator LEN
18.4 Clinical trials of HIV CA modulator LEN
18.5 LEN’s breakthrough in drug discovery
18.6 Conclusion and perspective
References
Chapter 19. Nirmatrelvir, SIM0417, and RAY1216: potent and selective SARS-CoV-2 main protease inhibitors for the potential treatment of COVID-19
Abstract
19.1 Introduction
19.2 Nirmatrelvir, SIM0417, and RAY1216 as SARS-CoV-2 Mpro inhibitors
19.3 Conclusion
Acknowledgments
References
Chapter 20. Bavdegalutamide (ARV-110): a potent PROTAC androgen receptor degrader for the treatment of metastatic-castration resistant prostate cancer
Abstract
Abbreviations
20.1 Introduction
20.2 Androgen receptor and prostate cancer
20.3 Proteolysis targeting chimeras
20.4 Advances in PROTAC androgen receptor degraders
20.5 Discovery and development of ARV-110
20.6 Conclusion
Acknowledgments
References
Further reading
Chapter 21. Darolutamide: an androgen receptor antagonist for the treatment of prostate cancer
Abstract
Abbreviations
21.1 Introduction
21.2 Current available therapies for prostate cancer
21.3 Androgen receptor antagonists
21.4 Introduction to darolutamide
21.5 Clinical efficacy of darolutamide
21.6 Safety profile of darolutamde
21.7 Conclusion
21.8 Future perspective
Acknowledgments
Funding
Conflict of interest
References
Chapter 22. Palbociclib, ribociclib, and abemaciclib: potent and selective CDK4/6 inhibitors for the treatment of breast cancer
Abstract
22.1 Introduction
22.2 Targeting CDK4/6 for breast cancer treatment
22.3 CDK4/6 inhibitors for breast cancer
22.4 Drug combination
22.5 Resistance to CDK4/6 inhibitors
22.6 Selective degradation of CDK4/6
22.7 Other CDK4/6 inhibitors
22.8 Conclusion
Acknowledgments
References
Chapter 23. Zanubrutinib: a breakthrough in cancer therapy targeting Bruton’s tyrosine kinase, originating from China, and benefiting the global community
Abstract
23.1 Introduction
23.2 Bruton’s tyrosine kinase
23.3 Zanubrutinib: drug discovery
23.4 Zanubrutinib: clinical trials
23.5 Discussion
References
Chapter 24. Discovery of FT-2102 (olutasidenib), an inhibitor of mutant isocitrate dehydrogenase 1, for treatment of relapsed or refractory acute myeloid leukemia
Abstract
24.1 Introduction
24.2 Main body
24.3 Conclusion
Acknowledgment
References
Chapter 25. Ziftomenib (KO-539): a potent and selective Menin inhibitor for the treatment of recurrent or refractory acute myeloid leukemia
Abstract
25.1 Introduction
25.2 The discovery of ziftomenib (KO-539)
25.3 The discovery stories of other Menin inhibitors
25.4 Conclusion
Acknowledgments
References
Chapter 26. Pulrodemstat (CC-90011): a highly potent, selective, and reversible lysine-specific demethylase 1 (LSD1) inhibitor
Abstract
26.1 Introduction
26.2 The structure architectures of lysine-specific demethylase 1
26.3 The catalytic mechanism of lysine-specific demethylase 1
26.4 The biological function of lysine-specific demethylase 1
26.5 Lysine-specific demethylase 1-targerd drug discovery
26.6 The discovery of pulrodemstat
26.7 Clinical trials of pulrodemstat
26.8 Conclusions
Acknowledgments
References
Chapter 27. Mavacamten, a first-in-class cardiac myosin inhibitor for the treatment of hypertrophic cardiomyopathy
Abstract
27.1 Introduction
27.2 The causes of hypertrophic cardiomyopathy
27.3 Mavacamten mode of action
27.4 Development of mavacamten
27.5 Clinical studies for mavacamten
27.6 Deuteration of mavacamten
27.7 Other cardiac myosin modulators
27.8 Conclusions
Acknowledgments
References
Chapter 28. Verquvo, a first-in-class soluble guanylate cyclase stimulator for the treatment of heart failure
Abstract
28.1 Introduction
28.2 Overview of vericiguat
28.3 Drug development and synthesis
28.4 Preclinical studies and clinical trials
28.5 Pharmacokinetic, toxicity properties, and drug interactions
28.6 Summary and future perspective
Rreferences
Chapter 29. Tafamidis: a transthyretin stabilizer for rare cardiac amyloidosis
Abstract
29.1 Introduction
29.2 The structure and related mechanisms of tafamidis
29.3 Clinical therapeutics of transthyretin amyloid cardiomyopathy
29.4 Summary and prospect
Funding information
References
Chapter 30. Oliceridine (TRV130): a biased agonist of the μ opioid receptor as a novel analgesic
Abstract
30.1 Introduction
30.2 Biased signaling of G-protein-coupled receptors
30.3 Medicinal chemistry discovery of TRV130
30.4 Selectivity and biased pharmacology of TRV130
30.5 Preclinical ADMET studies
30.6 Preclinical animal efficacy studies
30.7 Clinical pharmacokinetic studies
30.8 Clinical efficacy studies
30.9 Other reported biased µ-opioid receptor agonists
30.10 Structural biology study of biased signaling at µ-opioid receptor
30.11 Other possible mechanisms for the improved safety profile of TRV130
30.12 Summary
References
Chapter 31. Sotyktu (Deucravacitinib): the first tyrosine kinase 2 (TYK2) inhibitor approved for the treatment of psoriasis
Abstract
31.1 Introduction
31.2 Tyrosine kinase 2 as a popular target in psoriasis
31.3 Mechanism of action in Sotyktu
31.4 Discovery of Sotyktu
31.5 The SARs of Sotyktu as tyrosine kinase 2 JH2 ligands
31.6 Pharmacodynamics and pharmacokinetics of Sotyktu
31.7 Clinical trials of Sotyktu
31.8 Development of Sotyktu derivatives
31.9 Conclusion and perspective
References
Chapter 32. Bexagliflozin: a sodium-glucose co-transporter-2 inhibitor as anti-diabetic drug derived from phlorizin
Abstract
32.1 Introduction
32.2 Sodium-glucose co-transporter-2: a promising target for diabetes treatment
32.3 Structural modifications of phlorizin
32.4 The production process route for large-scale production of Bexagliflozin
32.5 Transitioning from the laboratory to the clinical setting
32.6 Conclusion
References
Chapter 33. Antidiabetic drugs−targeted PPARγ: from full agonists to selective modulators
Abstract
33.1 Introduction
33.2 The discovery of Chiglitazar
33.3 Pharmacokinetics evaluation in vitro and in vivo
33.4 Perinatal toxicity test in animal
33.5 Clinical trials
33.6 Ongoing clinical trials
33.7 Conclusion
Acknowledgments
References
Chapter 34. Pretomanid: an antibiotic used for the treatment of multidrug-resistant tuberculosis
Abstract
34.1 Introduction
34.2 The pathway of designing and development of pretomanid
34.3 Pharmacodynamics: mechanism of inhibition
34.4 Pharmacokinetics
34.5 Chemical synthesis of pretomanid
34.6 Pretomanid resistance: mechanism and its emergence
34.7 Antimicrobial activity against other bacterial species
34.8 Benefits and risks calculations
34.9 Conclusion
Acknowledgment
References
Chapter 35. Lecanemab (Leqembi): an amyloid beta monoclonal antibody approved for the treatment of Alzheimer’s disease
Abstract
35.1 Introduction
35.2 The research history of Lecanemab
35.3 Discussion
References
Chapter 36. Pembrolizumab: a breakthrough in cancer immunotherapy
Abstract
36.1 Introduction
36.2 Overview of programmed cell death protein-1/programmed cell death protein-L1 pathway
36.3 Effects of signaling pathways on programmed cell death protein-1/programmed cell death protein-L1 in cancer
36.4 Effects of microRNAs on programmed cell death protein-1/programmed cell death protein-L1 in cancer
36.5 Function of programmed cell death protein-1/programmed cell death protein-L1 in cancer
36.6 Pembrolizumab
36.7 FDA-approved indications (with clinical trial summaries)
36.8 Non-small-cell lung cancer
36.9 Head and neck squamous cell carcinoma
36.10 Renal cell carcinoma
36.11 Urothelial carcinoma
36.12 FDA-approved indications under accelerated approval (with clinical trial summaries)
36.13 Primary mediastinal large B-cell lymphoma
36.14 Urothelial carcinoma
36.15 Microsatellite instability-high cancer
36.16 Gastric cancer
36.17 Cervical cancer
36.18 Hepatocellular carcinoma
36.19 Merkel cell carcinoma
36.20 Small cell lung cancer
36.21 Non-FDA-approved indications in later-stage clinical trials
36.22 Mechanism of action
36.23 Conclusion
References
Index

Life Sciences

Physical Sciences & Engineering

Social Sciences & Humanities

Health

Drug Discovery Stories

From Bench to Bedside

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Bin Yu

Peng Zhan

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