Protein Homeostasis in Drug Discovery (eBook)

Milka Kostic, PhD, is the Program Director for Chemical Biology at the Dana-Farber Cancer Institute and her interests include advocating for the importance of chemical biology as a critical link in the chemistry-biology-medicine continuum. Lyn H. Jones, PhD, is currently Director of the Center for Protein Degradation at the Dana-Farber Cancer Institute and his interests include using chemogenomics and chemoproteomics to advance new therapeutic modalities.

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