Small-molecule inhibitors of protein-protein interactions: progressing toward the reality.

By Michelle Arkin, Yinyan Tang, J. Wells. Chemistry and Biology, 2014

931 citations recorded by the source corpus.

The past 20 years have seen many advances in our understanding of protein-protein interactions (PPIs) and how to target them with small-molecule therapeutics. In 2004, we reviewed some early successes; since then, potent inhibitors have been developed for diverse protein complexes, and compounds are now in clinical trials for six targets. Surprisingly, many of these PPI clinical candidates have efficiency metrics typical of "lead-like" or "drug-like" molecules and are orally available. Successful discovery efforts have integrated multiple disciplines and make use of all the modern tools of target-based discovery-structure, computation, screening, and biomarkers. PPIs become progressively more challenging as the interfaces become more complex, i.e., as binding epitopes are displayed on primary, secondary, or tertiary structures. Here, we review the last 10 years of progress, focusing on the properties of PPI inhibitors that have advanced to clinical trials and prospects for the future of PPI drug discovery.

Subfields: Molecular Biology, Organic Chemistry

View Paper: https://www.semanticscholar.org/paper/b7df3cd34a590f30d2f5ecdaf25afe7b60b8a5db

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Citations in the corpus

• The design and development of covalent protein-protein interaction inhibitors for cancer treatment (2020, background): “In the tertiary structure of epitopes, the binding interface is not continuous and requires multiple sites to form the PPI interface [24].”