Identification of RP-6685, an Orally Bioavailable Compound that Inhibits the DNA Polymerase Activity of Polθ

• Published in: Journal of medicinal chemistry Vol. 65; no. 19; pp. 13198 - 13215
• Main Authors: Bubenik, Monica, Mader, Pavel, Mochirian, Philippe, Vallée, Fréderic, Clark, Jillian, Truchon, Jean-François, Perryman, Alexander L., Pau, Victor, Kurinov, Igor, Zahn, Karl E., Leclaire, Marie-Eve, Papp, Robert, Mathieu, Marie-Claude, Hamel, Martine, Duffy, Nicole M., Godbout, Claude, Casas-Selves, Matias, Falgueyret, Jean-Pierre, Baruah, Prasamit S., Nicolas, Olivier, Stocco, Rino, Poirier, Hugo, Martino, Giovanni, Fortin, Alexanne Bonneau, Roulston, Anne, Chefson, Amandine, Dorich, Stéphane, St-Onge, Miguel, Patel, Purvish, Pellerin, Charles, Ciblat, Stéphane, Pinter, Thomas, Barabé, Francis, El Bakkouri, Majida, Parikh, Paranjay, Gervais, Christian, Sfeir, Agnel, Mamane, Yael, Morris, Stephen J., Black, W. Cameron, Sicheri, Frank, Gallant, Michel
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 13.10.2022; Amer Chemical Soc
• Subjects: Animals; Chemistry, Medicinal; DNA Replication; DNA-Directed DNA Polymerase - metabolism; Drug Design; Drug Discovery; Female; Humans; Life Sciences & Biomedicine; Mice; Ovarian Neoplasms; Pharmacology & Pharmacy; Science & Technology
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.2c00998

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.