2. Academic Validation
  3. Discovery of the Potent and Selective ATR Inhibitor Camonsertib (RP-3500)

Discovery of the Potent and Selective ATR Inhibitor Camonsertib (RP-3500)

  • J Med Chem. 2024 Feb 22;67(4):2349-2368. doi: 10.1021/acs.jmedchem.3c01917.
W Cameron Black 1,  Abbas Abdoli 2,  Xiuli An 3,  Anick Auger 4,  Patrick Beaulieu 5,  Michel Bernatchez 5,  Cathy Caron 1,  Amandine Chefson 4,  Sheldon Crane 2,  Mohamed Diallo 1,  Stéphane Dorich 4,  Lee D Fader 4,  Gino B Ferraro 1,  Sara Fournier 1,  Qi Gao 6,  Yelena Ginzburg 7,  Martine Hamel 1,  Yongshuai Han 3,  Paul Jones 2,  Stéphanie Lanoix 2,  Cyrus M Lacbay 2,  Marie-Eve Leclaire 1,  Maayan Levy 7,  Yael Mamane 1,  Amina Mulani 2,  Robert Papp 1,  Charles Pellerin 4,  Audrey Picard 4,  Alexander Skeldon 4,  Kathryn Skorey 2,  Rino Stocco 1,  Miguel St-Onge 4,  Jean-François Truchon 1,  Vouy Linh Truong 2,  Michal Zimmermann 1,  Michael Zinda 1,  Anne Roulston 1
Affiliations

Affiliations

  • 1 Repare Therapeutics, Inc., 7171 Frederick-Banting, Building 2, Saint-Laurent, Quebec H4S 1Z9, Canada.
  • 2 Nuchem Sciences, Inc., 2350 Rue Cohen, Suite 201, Saint-Laurent, Quebec H4R 2N6, Canada.
  • 3 New York Blood Center Enterprises, New York, New York 10065, United States.
  • 4 Ventus Therapeutics, Inc., 7150 Frederick-Banting, Saint-Laurent, Quebec H4S 2A1, Canada.
  • 5 OmegaChem, 480 Rue Perreault, Lévis, Quebec G6W 7V6, Canada.
  • 6 J-Star Research, Inc., 3001 Hadley Road, Suites 1-5A, South Plainfield, New Jersey 07080, United States.
  • 7 Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States.
PMID: 38299539 DOI: 10.1021/acs.jmedchem.3c01917
Abstract

ATR is a key kinase in the DNA-damage response (DDR) that is synthetic lethal with several other DDR proteins, making it an attractive target for the treatment of genetically selected solid tumors. Herein we describe the discovery of a novel ATR Inhibitor guided by a pharmacophore model to position a key hydrogen bond. Optimization was driven by potency and selectivity over the related kinase mTOR, resulting in the identification of camonsertib (RP-3500) with high potency and excellent ADME properties. Preclinical evaluation focused on the impact of camonsertib on myelosuppression, and an exploration of intermittent dosing schedules to allow recovery of the erythroid compartment and mitigate anemia. Camonsertib is currently undergoing clinical evaluation both as a single agent and in combination with talazoparib, olaparib, niraparib, lunresertib, or gemcitabine (NCT04497116, NCT04972110, NCT04855656). A preliminary recommended phase 2 dose for monotherapy was identified as 160 mg QD given 3 days/week.

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