biostudies-literatureBubenik MOno PharmaceuticalNCI NIH HHSCanadian Institutes of Health ResearchNIGMS NIH HHSNIH HHS13198-13215https://www.ebi.ac.uk/biostudies/studies/S-EPMC9942948biostudies-literatureUnknown65(19)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 <b>RP-6685</b>: a potent, selective, and orally bioavailable Polθ inhibitor that showed in vivo efficacy in an HCT116 BRCA2^-/- mouse tumor xenograft model.Journal of medicinal chemistryIdentification of <b>RP-6685</b>, an Orally Bioavailable Compound that Inhibits the DNA Polymerase Activity of Polθ.PMC9942948PJT-178026P30 CA008748P30 GM124165FDN-143277S10 OD021527PJT-180338Martino GCasas-Selves MCiblat SClark JChefson APoirier HRoulston AMorris SJMochirian PLeclaire MEParikh PPapp RBubenik MBaruah PSPatel PGervais CStocco RPinter TSicheri FDorich SGallant MDuffy NMEl Bakkouri MVallee FFalgueyret JPBarabe FNicolas OMathieu MCSt-Onge MSfeir ATruchon JFPellerin CPau VZahn KEGodbout CBlack WCKurinov IPerryman ALMamane YFortin ABMader PHamel MfalseIdentification of <b>RP-6685</b>, an Orally Bioavailable Compound that Inhibits the DNA Polymerase Activity of Polθ.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 <b>RP-6685</b>: a potent, selective, and orally bioavailable Polθ inhibitor that showed in vivo efficacy in an HCT116 BRCA2^-/- mouse tumor xenograft model.2022-01-01T00:00:00Z2022 Oct2026-05-28T16:21:58.924Z2024-12-03T21:31:50.385ZS-EPMC99429483612605910.1021/acs.jmedchem.2c00998