2. Academic Validation
  3. Discovery of an Orally Bioavailable and Selective PKMYT1 Inhibitor, RP-6306

Discovery of an Orally Bioavailable and Selective PKMYT1 Inhibitor, RP-6306

  • J Med Chem. 2022 Aug 11;65(15):10251-10284. doi: 10.1021/acs.jmedchem.2c00552.
Janek Szychowski 1,  Robert Papp 1,  Evelyne Dietrich 1,  Bingcan Liu 1,  Frédéric Vallée 1,  Marie-Eve Leclaire 1,  Jimmy Fourtounis 1,  Giovanni Martino 1,  Alexander L Perryman 1,  Victor Pau 2,  Shou Yun Yin 1,  Pavel Mader 2,  Anne Roulston 1,  Jean-Francois Truchon 1,  C Gary Marshall 3,  Mohamed Diallo 1,  Nicole M Duffy 1,  Rino Stocco 1,  Claude Godbout 1,  Alexanne Bonneau-Fortin 1,  Rosie Kryczka 1,  Vivek Bhaskaran 1,  Daniel Mao 2,  Stephen Orlicky 2,  Patrick Beaulieu 4,  Pascal Turcotte 5,  Igor Kurinov 6,  Frank Sicheri 2 7,  Yael Mamane 1,  Michel Gallant 1,  W Cameron Black 1
Affiliations

Affiliations

  • 1 Repare Therapeutics, Inc., 7210 Frederick-Banting, Ville St-Laurent, QC H4S 2A1, Canada.
  • 2 Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON M5G 1X5, Canada.
  • 3 Repare Therapeutics, 1 Broadway, 15th Floor, Cambridge, Massachusetts 02142, United States.
  • 4 OmegaChem Inc., 480 Rue Perreault, Saint-Romuald, QC G6W 7V6, Canada.
  • 5 AdMare BioInnovations, 7171 Frederick-Banting, Montréal, QC H4S 1Z9, Canada.
  • 6 Department of Chemistry and Chemical Biology, Cornell University, NE-CAT, Argonne, Illinois 60439, United States.
  • 7 Departments of Biochemistry and Molecular Genetics, University of Toronto, Ontario M5S 1A8, Canada.
PMID: 35880755 DOI: 10.1021/acs.jmedchem.2c00552
Abstract

PKMYT1 is a regulator of CDK1 phosphorylation and is a compelling therapeutic target for the treatment of certain types of DNA damage response cancers due to its established synthetic lethal relationship with CCNE1 amplification. To date, no selective inhibitors have been reported for this kinase that would allow for investigation of the pharmacological role of PKMYT1. To address this need compound 1 was identified as a weak PKMYT1 inhibitor. Introduction of a dimethylphenol increased potency on PKMYT1. These dimethylphenol analogs were found to exist as atropisomers that could be separated and profiled as single enantiomers. Structure-based drug design enabled optimization of cell-based potency. Parallel optimization of ADME properties led to the identification of potent and selective inhibitors of PKMYT1. RP-6306 inhibits CCNE1-amplified tumor cell growth in several preclinical xenograft models. The first-in-class clinical candidate RP-6306 is currently being evaluated in Phase 1 clinical trials for treatment of various solid tumors.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-145817A
    99.90%, PKMYT1 Inhibitor