2. Academic Validation
  3. Identification of RP-6685, an Orally Bioavailable Compound that Inhibits the DNA Polymerase Activity of Polθ

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

  • J Med Chem. 2022 Oct 13;65(19):13198-13215. doi: 10.1021/acs.jmedchem.2c00998.
Monica Bubenik 1,  Pavel Mader 2,  Philippe Mochirian 1,  Fréderic Vallée 1,  Jillian Clark 1,  Jean-François Truchon 1,  Alexander L Perryman 1,  Victor Pau 2,  Igor Kurinov 3,  Karl E Zahn 1,  Marie-Eve Leclaire 1,  Robert Papp 1,  Marie-Claude Mathieu 1,  Martine Hamel 1,  Nicole M Duffy 1,  Claude Godbout 1,  Matias Casas-Selves 1,  Jean-Pierre Falgueyret 1,  Prasamit S Baruah 1,  Olivier Nicolas 1,  Rino Stocco 1,  Hugo Poirier 1,  Giovanni Martino 1,  Alexanne Bonneau Fortin 1,  Anne Roulston 1,  Amandine Chefson 4,  Stéphane Dorich 4,  Miguel St-Onge 4,  Purvish Patel 4,  Charles Pellerin 4,  Stéphane Ciblat 4 5,  Thomas Pinter 4,  Francis Barabé 5,  Majida El Bakkouri 5 6,  Paranjay Parikh 7,  Christian Gervais 6,  Agnel Sfeir 8,  Yael Mamane 1,  Stephen J Morris 1,  W Cameron Black 1,  Frank Sicheri 2,  Michel Gallant 1
Affiliations

Affiliations

  • 1 Repare Therapeutics, 7171 Frederick-Banting, Building 2, Montréal, Québec H4S 1Z9, Canada.
  • 2 Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario M5G 1X5, Canada.
  • 3 Department of Chemistry and Chemical Biology, NE-CAT, Argonne, Cornell University, Illinois, New York 60439, United States.
  • 4 Ventus Therapeutics, 7150 Frederick-Banting Suite 200, Montréal, Québec H4S 2A1, Canada.
  • 5 Paraza Pharma Inc., 2525 Ave. Marie Curie, Montréal, Québec H4S 1Z9, Canada.
  • 6 National Research Council of Canada, 6100 Royalmount Avenue, Montréal, Québec H4P 2R2, Canada.
  • 7 Piramal Pharma Ltd., Plot No. 18, Village Matoda, Taluka: Sanand, Ahmedabad, Gujarat 382213, India.
  • 8 Molecular Biology Program, Sloan Kettering Institute, MSKCC, 430 E 67th Street, New York, New York 10065, United States.
PMID: 36126059 DOI: 10.1021/acs.jmedchem.2c00998
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.

Figures
Products