Abstract 677: Discovery of a first-in-class allosteric inhibitor of the small GTPase Rac1

• Published in: Cancer research (Chicago, Ill.) Vol. 84; no. 6_Supplement; p. 677
• Main Authors: Silverman, Robert, Cooper, Alan, Kar, Ronodip, Raman, Mayuri V., Ravirala, Ramu, Shah, Mubarak Hasan, Mahankali, Sandeep, Goka, Erik T.
• Format: Journal Article
• Language: English
• Published: 22-03-2024
• ISSN: 1538-7445; 1538-7445
• DOI: 10.1158/1538-7445.AM2024-677

The Rac1 signaling pathway is known to be hyperactivated in numerous solid tumors. We developed a Rac1 AlphaLISA assay that is amenable to high-throughput screening (HTS) to screen large libraries of small molecules. Based on molecular modeling of a putative allosteric binding site for several of the hits, we optimized a series of compounds that lead to RP-102124. RP-102124 engages with Rac1 in both biochemical and cellular target engagement assays. RP-102124 has greater potency than previously reported Rac1 inhibitors in biochemical assays, with potent inhibition of phenotypic characteristics of Rac signaling such as cell migration and cytoskeletal rearrangements. RP-102124 is a Racmulti inhibitor with activity against oncogenic Rac1b. RP-102124 is orally bioavailable and shows dose dependent inhibition of tumor growth in xenograft models at doses that are well-tolerated. RP-102124 is a first-in-class allosteric Racmulti inhibitor that shows promising therapeutic potential.
Citation Format: Robert Silverman, Alan Cooper, Ronodip Kar, Mayuri V. Raman, Ramu Ravirala, Mubarak Hasan Shah, Sandeep Mahankali, Erik T. Goka. Discovery of a first-in-class allosteric inhibitor of the small GTPase Rac1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 677.