CRCM, Institute Paoli-Calmettes, CNRS, INSERM, Aix Marseille Univ, Marseille, France
Targeting protein-protein interactions: The 2P2I approach
Protein-protein interactions (PPIs) are involved in almost all cellular processes and represent attractive targets for the treatment of major diseases including various types of cancer. Several PPI inhibitors (iPPIs) have entered clinical trials, and some have been approved, such as venetoclax, and a growing number of PPIs have been validated as therapeutic drug targets. Despite this, PPIs remain challenging to target with small molecules. High-throughput screening (HTS) is an essential tool for drug discovery. However, for PPIs, the success rate is generally low, primarily due to the use of unsuitable screening libraries. In this talk, I will present our efforts to tackle this refractory chemical space. The presentation will address the design of chemical libraries dedicated to the inhibition of PPIs, the development of integrated chemistry-driven hit-to-lead strategies to rapidly generate improved compounds. Finally, I will discuss recent strategies implemented for the development of covalent probes. Several examples of probe development will be provided as proof of concept to illustrate the different approaches.
- Morelli, X., Bourgeas, R., and Roche, P. (2011) Chemical and structural lessons from recent successes in protein-protein interaction inhibition (2P2I). Curr Opin Chem Biol. 15: 475-481
- Basse, M.J., Betzi, S., Bourgeas, R., Bouzidi, S., Chetrit, B., Hamon, V., Morelli, X., and Roche, P. (2013) 2P2Idb: a structural database dedicated to orthosteric modulation of protein-protein interactions. Nucleic Acids Res. 41: D824-827
- Hoffer, L., Voitovich, Y.V., Raux, B., Carrasco, K., Muller, C., Fedorov, A.Y., Derviaux, C., Amouric, A., Betzi, S., Horvath, D., Varnek, A., Collette, Y., Combes, S., Roche, P., and Morelli, X. (2018) Integrated Strategy for Lead Optimization Based on Fragment Growing: The Diversity-Oriented-Target-Focused-Synthesis Approach. J Med Chem. 61: 5719-5732
- Hoffer, L., Saez-Ayala, M., Horvath, D., Varnek, A., Morelli, X., and Roche, P. (2019) CovaDOTS: In Silico Chemistry-Driven Tool to Design Covalent Inhibitors Using a Linking Strategy. J Chem Inf Model. 59: 1472-1485
- Bosc, N., Muller, C., Hoffer, L., Lagorce, D., Bourg, S., Derviaux, C., Gourdel, M.E., Rain, J.C., Miller, T.W., Villoutreix, B.O., Miteva, M.A., Bonnet, P., Morelli, X., Sperandio, O., and Roche, P. (2020) Fr-PPIChem: An Academic Compound Library Dedicated to Protein-Protein Interactions. ACS Chem Biol. 15: 1566-1574
- Carrasco, K., Montersino, C., Derviaux, C., Saez-Ayala, M., Hoffer, L., Restouin, A., Castellano, R., Casassa, J., Roche, P., Pasquier, E., Combes, S., Morelli, X., Collette, Y., and Betzi, S. (2022) CRCM5484: A BET-BDII Selective Compound with Differential Anti-leukemic Drug Modulation. J Med Chem. 65: 5660-5674.