Advances in the Discovery of Protein-Protein Interaction Modulators

This report discusses technologies and strategies that enable the discovery of drugs targeting protein-protein interactions (PPIs), covering both small-molecule and synthetic peptidic modulators. The report provides case studies of specific target classes and draws lessons from both the successes achieved and the remaining challenges.

Features and benefits

• Understand why the discovery of PPI modulators has been difficult, and why it is crucial for pharmaceutical companies to overcome these hurdles now.
• Gain insight into the most effective strategies and technologies for discovering PPI modulators.
• Identify companies and academic laboratories that are leaders in the PPI modulator field.
• Identify and evaluate ongoing programs seeking to discover and develop drugs tageting PPIs.
• Understand the limitations of challenges remaining in the field, and thereby identify opportunities for future progress.

Highlights

Despite the difficulty of the PPI modulator field, one direct PPI agonist –eltrombopag (Ligand/GSK’s Promacta/Revolade) – and two allosteric PPI antagonists – maraviroc (Pfizer’s Selzentry/Celsentri) and plerixafor (Genzyme’s Mozobil) – have reached the market. Several other compounds are in the clinic.

The discovery of currently marketed and clinical-stage compounds was made possible by a set of tools including X-ray diffraction, alanine scanning mutagenesis, fragment-based drug discovery, and conventional medicinal chemistry. Central to this research has been the determination of “hot spots” in protein-protein interfaces

Recently, companies such as Forma, Ensemble, and Aileron, as well as academic laboratories, have been developing second-generation technologies for the discovery of PPI modulators. These technologies are designed to provide a more accelerated and systematic approach to PPI drug discovery and development.

Your key questions answered

• Why has the discovery and development of PPI modulator drugs been found so difficult historically?
• What is to be gained by investing in the discovery of drugs acting at such challenging targets?
• Who have been in the pioneers in the PPI field, and what strategies have they employed to turn PPIs into viable targets?
• Which companies have developed clinical-stage and marketed drugs that modulate protein-protein interactions?
• What second-generation technologies are being developed to accelerate progress in the PPI drug field and where is the field heading?

Table Of Contents

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EXECUTIVE SUMMARY
Introduction
General strategies for targeting protein-protein interactions with small molecules
Small molecules targeting protein-protein interactions of cell-surface receptors
Small molecules targeting intracellular signaling pathways
Small molecules targeting the ubiquitin system
Small molecules targeting protein-protein interactions that control apoptosis
Stapled peptides for targeting protein-protein interactions
Outlook for protein-protein interaction modulators

Introduction
Summary
The new strategic importance of protein-protein interactions
The challenges of targeting protein-protein interactions
Theoretical reasons for the “undruggabilty” of protein-protein interactions
Overcoming the theoretical challenges to PPI druggability
Structure of this report

General strategies for targeting protein-protein interactions with small molecules
Summary
Introduction
Structural biology studies to determine “hotspots” in protein-protein binding interfaces
Insights from the study of interleukin-2 (IL-2) and its binding to the IL-2 receptor alpha chain (IL-2Rα)
Mutagenesis and structural studies
Ro26-4550 and the nature of the IL-2/IL-2Rα hotspot
Fragment-based discovery of small-molecule PPI-modulating drugs
Tethering
SAR by NMR
Computational identification of hot spots for fragment-based drug design
Discovery of allosteric modulators of PPIs
Design of improved chemical libraries for targeting PPIs
Diversity-oriented synthesis versus fragment-based drug design
The “Build, Couple, Pair” strategy for diversity-oriented synthesis
The new focus on macrocycles in academia and industry
Ensemble’s macrocycle synthesis technology
Cellular assays in screening for drugs that modulate PPIs
Ligand’s STATs technology
BioImage’s Redistribution technology
Forma Therapeutics: moving small-molecule PPI modulator discovery up the technology development curve
Conclusions

Small molecules targeting protein-protein interactions of cell-surface receptors
Summary
Introduction
Small-molecule agonists of cytokine receptors
Ligand’s small-molecule thrombopoietin (TPO) receptor agonists
Ligand’s preclinical small-molecule EPO and G-CSF receptor agonists
Small-molecule integrin antagonists
Chemokine receptor antagonists
Small-molecule antagonists of the TNF/TNFR PPI
Conclusions

Small molecules targeting intracellular signaling pathways
Summary
Introduction
Small-molecule inhibitors of the oncogenic Tcf/β-catenin transcription factor complex
Preclinical studies of PKF115-584 and CGP049090
Small-molecule inhibitors of the BCL6/SMRT PPI in B-cell lymphoma
BCL6/SMRT antagonists and the issue of targeting epigenetic regulation
Small-molecule AKAP-protein kinase A interaction disruptors for potential treatment of chronic heart failure
Conclusions

Small molecules targeting the ubiquitin system
Summary
Introduction
The ubiquitin system
Proteasome inhibitors and the ubiquitin-proteasome system
Ubiquitin-proteasome system inhibitors of intermediate specificity
Development of specific inhibitors of E3s
Small-molecule antagonists of the HDM2/p53 PPI
Structural studies of the HDM2/p53 PPI
Nutlins
MI-219
JNJ-26854165
MDM4/MDMX and therapy with HDM2/p53 inhibitors
Inhibitors of other E3 ubiquitin ligases via disruption of PPIs
Conclusions

Small molecules targeting protein-protein interactions that control apoptosis
Summary
Introduction
Apoptotic pathways
The intrinsic pathway of apoptosis
The extrinsic pathway of apoptosis
Abbott/Genentech’s Bcl-2 inhibitor ABT-263 (navitoclax)
Obatoclax, a pan-Bcl-2 inhibitor that inhibits MCl-1
Conclusions

Stapled peptides for targeting protein-protein interactions
Summary
Introduction
Aileron Therapeutics and stapled peptide technology
Targeting the notch pathway using a stapled peptide
Aileron’s therapeutic programs
The Aileron/Roche collaboration
Conclusions

Outlook for protein-protein interaction modulators
Summary
Discovery and development of PPI modulators has been difficult
Targeting PPIs is becoming increasingly important for the success of the pharmaceutical industry
Researchers have discovered PPI modulators and moved them into the clinic
New technologies are enabling the development of small-molecule and peptide PPI modulators
Pharmaceutical and biotechnology companies are moving back into the PPI modulator field

Appendix
Abbreviations
References
Chapter 1 references
Chapter 2 references
Chapter 3 References
Chapter 4 references
Chapter 5 references
Chapter 6 References
Chapter 7 references
Chapter 8 references

List Of Tables

Table: Challenges and solutions in developing drugs that target PPIs
Table: Well-studied PPI targets used to validate Vajda’s CS-mapping technology
Table: Selected large pharmaceutical companies with active small-molecule PPI modulator discovery programs
Table: Selected chemokine receptor modulators in development
Table: PPI modulators in development targeting cell-surface receptors that interact with non-chemokine proteins or peptides
Table: Aileron’s therapeutic pipeline
Table: Clinical-stage PPI modulators

List Of Figures

Figure: Chemical structure of Ro26-4550
Figure: Use of tethering to identify a lead in fragment-based drug design
Figure: Chemical structure of maraviroc
Figure: Build, couple, pair strategy
Figure: Chemical structure of robotnikinin
Figure: Chemical structure of SB-247464
Figure: Chemical structure of eltrombopag
Figure: Chemical structure of plerixafor
Figure: Chemical structure of 79-6
Figure: Chemical structure of FMP-API-1
Figure: The ubiquitinylation pathway
Figure: Chemical structure of nutlin-3
Figure: Chemical structure of ABT-737
Figure: Chemical structure of ABT-263 (navitoclax)
Figure: Chemical structure of obatoclax
Figure: Construction of a stapled peptide