Identification of RP-6685, an orally bioavailable compound that inhibits the DNA polymerase activity of Polθ Journal Article
| Authors: | Bubenik, M.; Mader, P.; Mochirian, P.; Vallée, F.; Clark, J.; Truchon, J. F.; Perryman, A. L.; Pau, V.; Kurinov, I.; Zahn, K. E.; Leclaire, M. E.; Papp, R.; Mathieu, M. C.; Hamel, M.; Duffy, N. M.; Godbout, C.; Casas-Selves, M.; Falgueyret, J. P.; Baruah, P. S.; Nicolas, O.; Stocco, R.; Poirier, H.; Martino, G.; Fortin, A. B.; Roulston, A.; Chefson, A.; Dorich, S.; St-Onge, M.; Patel, P.; Pellerin, C.; Ciblat, S.; Pinter, T.; Barabé, F.; El Bakkouri, M.; Parikh, P.; Gervais, C.; Sfeir, A.; Mamane, Y.; Morris, S. J.; Black, W. C.; Sicheri, F.; Gallant, M. |
| Article Title: | Identification of RP-6685, an orally bioavailable compound that inhibits the DNA polymerase activity of Polθ |
| 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. © 2022 American Chemical Society. |
| Keywords: | dna replication; ovarian neoplasms; mouse; animal; metabolism; animals; mice; drug discovery; drug development; drug design; ovary tumor; dna-directed dna polymerase; dna directed dna polymerase; humans; human; female |
| Journal Title: | Journal of Medicinal Chemistry |
| Volume: | 65 |
| Issue: | 19 |
| ISSN: | 0022-2623 |
| Publisher: | American Chemical Society |
| Date Published: | 2022-10-13 |
| Start Page: | 13198 |
| End Page: | 13215 |
| Language: | English |
| DOI: | 10.1021/acs.jmedchem.2c00998 |
| PUBMED: | 36126059 |
| PROVIDER: | scopus |
| PMCID: | PMC9942948 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 December 2022 -- Source: Scopus |
