8e24
Human DNA polymerase theta in complex with allosteric inhibitor
Structural highlights
FunctionDPOLQ_HUMAN Has a DNA polymerase activity on nicked double-stranded DNA and on a singly primed DNA template. The enzyme activity is resistant to aphidicolin, and inhibited by dideoxynucleotides. Exhibites a single-stranded DNA-dependent ATPase activity. Could be involved in the repair of interstrand cross-links.[1] Publication Abstract from PubMedDNA polymerase theta (Poltheta) 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 Poltheta (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 Poltheta inhibitor that showed in vivo efficacy in an HCT116 BRCA2(-/-) mouse tumor xenograft model. Identification of RP-6685, an Orally Bioavailable Compound that Inhibits the DNA Polymerase Activity of Poltheta.,Bubenik M, Mader P, Mochirian P, Vallee F, Clark J, Truchon JF, Perryman AL, Pau V, Kurinov I, Zahn KE, Leclaire ME, Papp R, Mathieu MC, Hamel M, Duffy NM, Godbout C, Casas-Selves M, Falgueyret JP, Baruah PS, Nicolas O, Stocco R, Poirier H, Martino G, Fortin AB, Roulston A, Chefson A, Dorich S, St-Onge M, Patel P, Pellerin C, Ciblat S, Pinter T, Barabe F, El Bakkouri M, Parikh P, Gervais C, Sfeir A, Mamane Y, Morris SJ, Black WC, Sicheri F, Gallant M J Med Chem. 2022 Sep 20. doi: 10.1021/acs.jmedchem.2c00998. PMID:36126059[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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