Identification of RP-6685 , an Orally Bioavailable Compound that Inhibits the DNA Polymerase Activity of Polθ.
Monica BubenikPavel MaderPhilippe MochirianFréderic ValléeJillian ClarkJean-François TruchonAlexander L PerrymanVictor PauIgor KurinovKarl E ZahnMarie-Eve LeclaireRobert PappMarie-Claude MathieuMartine HamelNicole M DuffyClaude GodboutMatias Casas-SelvesJean-Pierre FalgueyretPrasamit S BaruahOlivier NicolasRino StoccoHugo PoirierGiovanni MartinoAlexanne Bonneau FortinAnne RoulstonAmandine ChefsonStéphane DorichMiguel St-OngePurvish PatelCharles PellerinStéphane CiblatThomas PinterFrancis BarabéMajida El BakkouriParanjay ParikhChristian GervaisAgnel SfeirYael MamaneStephen J MorrisW Cameron BlackFrank SicheriMichel GallantPublished in: Journal of medicinal chemistry (2022)
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.
Keyphrases
- drug discovery
- circulating tumor
- molecular docking
- cell free
- single molecule
- endothelial cells
- quality improvement
- bioinformatics analysis
- working memory
- breast cancer risk
- emergency department
- transcranial magnetic stimulation
- induced pluripotent stem cells
- cell death
- adverse drug
- molecular dynamics simulations
- high frequency
- light emitting