Protein Homeostasis in Drug Discovery

Protein Homeostasis in Drug Discovery Comprehensive resource on all aspects of protein homeostasis, covering both historical perspectives and emerging technologies that are revolutionizing the field Protein Homeostasis in Drug Discovery highlights drug discovery and development efforts targeting protein homeostasis and considers the emerging appreciation that a protein’s activity may not be the only factor to consider when developing therapeutic agents. The chapters cover various aspects of protein homeostasis such as cellular localization, abundance, interactions, and more. Moreover, the text contains up-to-date information regarding targeted protein degradation, an emerging drug discovery modality. Readers interested in targeting different regulatory events that control protein homeostasis or modulating protein abundance will find this book an excellent resource. Furthermore, those interested in the link between biological function and regulating protein levels in living organisms, especially in the context of drug discovery, will learn from numerous examples discussed in this book. In Protein Homeostasis in Drug Discovery, readers can expect to find information on: Protein folding, quality control, pharmacology, and drug targeting processes Recent advances in our understanding of protein homeostasis, covering emerging technologies and opportunities for therapeutic intervention Targeted protein degradation (TPD) and strategies such as PROTACs and molecular glues, including a chapter on TPD as an antiviral drug discovery strategy Drug discovery and development efforts aimed at correcting, stabilizing, and rescuing proteins, with examples included Advantages and key shortcomings of both phenotypic and target-based traditional drug discovery methods Collectively, Protein Homeostasis in Drug Discovery offers the reader an opportunity to learn more about the importance of considering and targeting protein homeostasis. The text is a must-read resource for academics, professionals in the pharmaceutical industry, and advanced students in various science-related fields.

List of Contributors ix Preface xv Section I Protein Folding and Quality Control in Drug Discovery 1 1 Epichaperomes as a Gateway to Understanding, Diagnosing, and Treating Disease Through Rebalancing Protein–Protein Interaction Networks 3 Chander S. Digwal, Sahil Sharma, Anand R. Santhaseela, Stephen D. Ginsberg, and Gabriela Chiosis 2 Stability of Steroid Hormone Receptors: The Intersection of Proteostasis and Selective Degradation 27 Zachary J. Gale-Day and Jason E. Gestwicki 3 Pharmacological Chaperones: Therapeutic Potential for Diseases Resulting from GPCR Misfolding 65 Suli-Anne Laurin, Sajjad Ahrari, and Michel Bouvier Section II Protein Degradation and Clearance as Drug Targeting Opportunities 135 4 Exploiting the Proteasome for Disease Treatment: From Dynamic Architecture to Vast Functions 137 Gwen R. Buel, Xiuxiu Lu, and Kylie J. Walters 5 Targeting the Ubiquitination Cascade for Drug Discovery 179 Qi Liu, Gabriel LaPlante, and Wei Zhang 6 Understanding, Targeting, and Hijacking Autophagy 227 Hongguang Xia, Xiaoyan Xu, Mengxin Zhou, Manke Zhang, and Lingzhi Ye 7 Deubiquitinating Enzymes: From Undruggable Targets to Emerging Opportunities 249 Xiaoxi Liu, Laura Doherty, Alejandra Felix, and Sara Buhrlage Section III Redirecting Protein Degradation Processes for Drug Development 283 8 History of IMiDs and Protein Degradation as a Pharmacological Modality 285 Junichi Yamamoto, Tomoko Asatsuma-Okumura, Takumi Ito, Yuki Yamaguchi, and Hiroshi Handa 9 PROTAC Degraders: Mechanism, Recent Advances, and Future Challenges 317 Alessio Ciulli and Oliver Hsia 10 Biochemical Principles of Targeted Protein Degradation 357 Roman V. Agafonov, Richard W. Deibler, William A. Elam, Joe S. Patel, and Stewart L. Fisher 11 Pharmacology of PROTAC Degrader Molecules: Optimizing for In Vivo Performance 385 Andy Pike, Sofia Guzzetti, Pablo M. Morentin Gutierrez, and James S. Scott Section IV Emerging Technologies and Future Opportunities 419 12 Proximity-Inducing Bifunctional Molecules Beyond PROTACs 421 Sophia Lai, Ashley E. Modell, and Amit Choudhary 13 Strategies for Tag-Based Protein Control 447 Behnam Nabet, Nathanael S. Gray, and Fleur M. Ferguson 14 Targeted Protein Degradation in Antiviral Drug Discovery 465 Mélissanne de Wispelaere and Priscilla L. Yang 15 Beyond Inhibition: Ligand-Based Pharmacological Exploration as a Strategy Toward New Targets and Modalities 491 Milka Kostic and Lyn H. Jones Index 519