Clinical candidates modulating protein-protein interactions: The fragment-based experience

Area of Science:

• Biochemistry
• Medicinal Chemistry
• Pharmacology

Background:

• Protein-protein interactions (PPIs) are crucial for biological functions and represent key targets for novel therapeutics.
• The complex, dynamic nature of PPIs necessitates sophisticated strategies for developing selective modulators.
• Fragment-based approaches have emerged as a powerful methodology in drug discovery for targeting PPIs.

Purpose of the Study:

• To review successful fragment-to-clinical candidate evolutions in the development of protein-protein interaction modulators.
• To provide an overview of the physico-chemical properties of fragment hits and lead compounds.
• To present a statistical analysis of the distribution of these properties.

Main Methods:

• Literature review focusing on fragment-based drug discovery case studies targeting PPIs.
• Analysis of physico-chemical properties of identified fragment hits and lead compounds.
• Statistical evaluation of property distributions for fragment-derived drug candidates.

Main Results:

• Several fragment-based approaches have successfully progressed from initial hits to clinical candidates for modulating PPIs.
• Key physico-chemical properties distinguishing fragment hits from lead compounds were identified.
• Statistical analysis revealed trends in property distribution crucial for successful PPI drug development.

Conclusions:

• Fragment-based drug discovery is a validated and highly effective strategy for developing modulators of protein-protein interactions.
• Understanding the physico-chemical landscape of fragment hits and lead compounds is vital for optimizing drug development pipelines.
• This approach holds significant promise for advancing therapeutic strategies targeting complex PPIs.