Identification of <b>RP-6685</b>, an Orally Bioavailable Compound that Inhibits the DNA Polymerase Activity of Polθ
Monica Bubenik, P. Mäder, Philippe Mochirian, Frédéric Vallée, Jillian M.R. Clark, Jean‐François Truchon, Alexander L. Perryman, Victor P.T. Pau, Igor Kurinov, Karl E. Zahn, Marie-Ève Leclaire, Robert Papp, Marie‐Claude Mathieu, Martine Hamel, Nicole M. Duffy, Claude Godbout, Matias Casás‐Selves, Jean‐Pierre Falgueyret, Prasamit S. Baruah, Olivier Nicolas, Rino Stocco, Hugo Poirier, Giovanni De Martino, Alexanne Bonneau Fortin, Anne Roulston, Amandine Chefson, Stéphane Dorich, Miguel St‐Onge, Purvish P. Patel, Charles Pellerin, Stéphane Ciblat, Thomas Pinter, Francis Barabé, Majida El Bakkouri, Paranjay Parikh, Christian Gervais, Agnel Sfeir, Yaël Mamane, Stephen J. Morris, W. Cameron Black, Frank Sicheri, Michel Gallant
Abstract
DNA polymerase theta (Polθ) is an attractive synthetic lethal target for drug discovery, predicted to be efficacious against breast and ovarian cancers harboring BRCA-mutant alleles. Here, we describe our hit-to-lead efforts in search of a selective inhibitor of human Polθ (encoded by POLQ). A high-throughput screening campaign of 350,000 compounds identified an 11 micromolar hit, giving rise to the N2-substituted fused pyrazolo series, which was validated by biophysical methods. Structure-based drug design efforts along with optimization of cellular potency and ADME ultimately led to the identification of RP-6685: a potent, selective, and orally bioavailable Polθ inhibitor that showed in vivo efficacy in an HCT116 BRCA2–/– mouse tumor xenograft model.