Successful Drug Discovery, Volume 5

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Группа авторов. Successful Drug Discovery, Volume 5

Table of Contents

List of Tables

List of Illustrations

Guide

Pages

Successful Drug Discovery

Advisory Board Members

Preface

Part I: General Aspects

Part II: Drug Class Studies

Part III: Case Studies

1 Drug Discovery in Academia

1.1 Introduction

1.2 Repurposing Drugs

1.2.1 Thalidomide Derivatives

1.2.2 Chemotherapy: Nitrogen Mustards

1.3 Pregabalin

1.4 Natural Product‐Derived Drug Discovery

1.4.1 Antibiotics

1.4.2 Anticancer Drugs. 1.4.2.1 Camptothecin

1.4.2.2 Taxol

1.4.2.3 Epothilones

1.4.2.4 Eribulin

1.4.3 Artemisinin and Artemether

1.4.4 Carfilzomib

1.5 Biologic Drugs. 1.5.1 Insulin

1.5.2 Rituximab

1.5.3 Alglucerase

1.6 Conceptionally New Small Molecule Drugs

1.6.1 Histone Deacetylase Inhibitors

1.6.2 Acyclic Nucleoside Phosphonates

1.6.3 Darunavir

1.6.4 Sunitinib

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

2.5.1 The Ability to Expand the Druggable Proteome

2.5.2 Overcoming the Accumulation of Target Protein

2.5.3 Abrogating Scaffolding Functions

2.5.4 Creating Target Specificity

2.5.5 Catalytic Mode of Action

2.5.6 Event‐Driven Pharmacology and Prolonged PD Effect

2.6 Potential Disadvantages and Limitations of Degraders

2.7 Molecular Glue‐like Degraders and Monovalent Degraders

2.7.1 Definitions and Historical Perspective

2.7.2 State of the Art

2.8 Future Directions (Status Q3 2020)

2.9 Summary and Conclusions

Acknowledgments

List of Abbreviations

References

Biographies

3 GLP‐1 Receptor Agonists for the Treatment of Type 2 Diabetes and Obesity

3.1 Introduction

3.2 GLP‐1 Biology

3.2.1 GLP‐1 Receptor Binding and Activation

3.2.2 GLP‐1 Pharmaceutical Developments

3.3 Ex4‐Based Analogues. 3.3.1 Exenatide

3.3.2 Exenatide LAR

3.3.3 Lixisenatide

3.3.4 Efpeglenatide

3.3.5 Pegylated Loxenatide

3.4 GLP‐1 Based Analogues

3.4.1 Liraglutide

3.4.2 Semaglutide

3.4.3 Taspoglutide

3.4.4 Albiglutide and Albenatide

3.4.5 Dulaglutide

3.5 Co‐agonists

3.5.1 GLP‐1/GIP Co‐agonists

3.5.2 GLP‐1/Glucagon Co‐agonists

3.5.2.1 Other GLP‐1R 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

4.3.1 Dapagliflozin

4.3.2 Sotagliflozin

4.3.3 Empagliflozin

4.3.4 Bexagliflozin

4.3.5 Luseogliflozin

4.3.6 Tofogliflozin

4.3.7 Ertugliflozin

4.3.8 Ipragliflozin

4.3.9 Canagliflozin

4.3.10 Remogliflozin

4.4 Clinical Benefits of SGLT2 Inhibitors

4.4.1 Reduction in HbA1C Levels

4.4.2 Protection Against Cardiovascular Events in Diabetic Patients

4.4.3 Renoprotection in Patients with T2D

4.4.4 Bodyweight Reduction

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

List of Abbreviations

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. 5.3.1 T Cell Receptor‐Engineered T Cells

5.3.1.1 Intro to TCRs

5.3.1.2 Challenges with TCR‐Engineered T Cells

5.3.2 CAR T Cells

5.3.2.1 What Is a CAR?

5.3.2.2 Why Do You Put a CAR into a T Cell (as Opposed to Another Cell)?

5.4 CAR T Cells: The Living Drug

5.4.1 Early Signals of CAR T Cell Efficacy

5.4.2 CART19 Pharmacokinetics

5.4.2.1 Expansion

5.4.2.2 Persistence

5.4.2.3 Trafficking

5.4.3 Biomarkers of CAR T Cell Quality

5.4.4 Side Effects of CAR T Cell Therapy. 5.4.4.1 Cytokine Release Syndrome

5.4.4.2 CAR T Cell Associated Neurotoxicity

5.4.4.3 On‐Target, Off‐Tumor Toxicities

5.4.5 Challenges Encountered with Therapeutic Application of CAR T Cells

5.4.5.1 Production Issues

5.4.5.2 Therapeutic Resistance

5.5 Translation from Laboratory Innovation to Approved Therapy

5.6 Future Directions and CAR T Programs to Consider

5.6.1 Approved Therapies

5.6.2 Pre‐registration Therapies

5.7 Additional Resources for Supplementary Information on Cellular Therapies, Including Regulations, Notifications, and Guidelines

List of Abbreviations

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?

6.4.1 Small‐Molecule Antagonists

6.4.2 Large‐Molecule Antagonists

6.5 Role of CGRP Antagonists in Other Indications

6.6 Conclusions

List of Abbreviations

References

Biographies

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

7.2.1 Brief History on Discovery of Emicizumab. 7.2.1.1 Idea Inspiration of an Asymmetric Bispecific IgG Antibody to FIXa and FX with FVIII‐Cofactor Function

7.2.1.2 From the First Immunization to the Identification of the Clinical Candidate (ACE910 = Emicizumab)

7.2.2 Mechanism of Action and Nonclinical Characteristics of Emicizumab. 7.2.2.1 Mechanism of Action and In Vitro Characteristics of Emicizumab

7.2.2.2 In Vivo Characteristics of Emicizumab

7.2.3 Molecular Engineering Technologies Incorporated in Emicizumab for Industrial Manufacturing

7.2.3.1 Obtaining a Common Light Chain

7.2.3.2 Separation and Purification from By‐products

7.2.3.3 Minimizing the Amount of Homodimeric By‐products

7.2.3.4 Application of Technology

7.2.4 Conclusions from Preclinical Studies

7.3 Clinical Experience with Emicizumab

7.3.1 Early‐Phase Clinical Development. 7.3.1.1 Phase I and I/II Studies

Single‐Ascending‐Dose Studies

Multiple‐Ascending‐Dose Studies

7.3.1.2 Clinical Pharmacology Investigations

Model‐Informed Phase III Dose Selection

Relative and Absolute Bioavailability Study

7.3.2 Late‐Phase Clinical Development. 7.3.2.1 Non‐interventional Study

7.3.2.2 Phase III Studies with Once‐Weekly Dosing in Patients with FVIII Inhibitors

7.3.2.3 Phase III Studies with Once‐Weekly, Every‐2‐Week, or Every‐4‐Week Dosing in Patients with or without FVIII Inhibitors

7.4 Conclusions

Acknowledgments

Conflict of Interests

List of Abbreviations

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

List of Abbreviations

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

List of Abbreviations

References

Biographies

Index

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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.

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.

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