2. Academic Validation
  3. Discovery of a chemical probe for PRDM9

Discovery of a chemical probe for PRDM9

  • Nat Commun. 2019 Dec 17;10(1):5759. doi: 10.1038/s41467-019-13652-x.
Abdellah Allali-Hassani 1,  Magdalena M Szewczyk 1,  Danton Ivanochko 1 2,  Shawna L Organ 1,  Jabez Bok 3,  Jessica Sook Yuin Ho 3,  Florence P H Gay 3,  Fengling Li 1,  Levi Blazer 1,  Mohammad S Eram 1,  Levon Halabelian 1,  David Dilworth 1,  Genna M Luciani 1,  Evelyne Lima-Fernandes 1,  Qin Wu 1,  Peter Loppnau 1,  Nathan Palmer 3,  S Zakiah A Talib 3,  Peter J Brown 1,  Matthieu Schapira 1 4,  Philipp Kaldis 3 5,  Ronan C O'Hagan 6,  Ernesto Guccione 3 7 8,  Dalia Barsyte-Lovejoy 1 9,  Cheryl H Arrowsmith 1 2,  John M Sanders 6,  Solomon D Kattar 6,  D Jonathan Bennett 6,  Benjamin Nicholson 10,  Masoud Vedadi 11 12
Affiliations

Affiliations

  • 1 Structural Genomics Consortium, University of Toronto, Toronto, ON, M5G 1L7, Canada.
  • 2 Princess Margaret Cancer Centre and Department of Medical Biophysics, University of Toronto, Toronto, ON, M5G 2M9, Canada.
  • 3 Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore.
  • 4 Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, M5S 1A8, Canada.
  • 5 National University of Singapore (NUS), Department of Biochemistry, 117597, Singapore, Singapore.
  • 6 Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ, 07033, USA.
  • 7 Department of Oncological Sciences and Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
  • 8 Department of Pharmacological Sciences and Mount Sinai Center for Therapeutics Discovery, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
  • 9 Nature Research Center, Vilnius, Akademijos, 2, Lithuania.
  • 10 Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ, 07033, USA. [email protected].
  • 11 Structural Genomics Consortium, University of Toronto, Toronto, ON, M5G 1L7, Canada. [email protected].
  • 12 Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, M5S 1A8, Canada. [email protected].
PMID: 31848333 DOI: 10.1038/s41467-019-13652-x
Abstract

PRDM9 is a PR domain containing protein which trimethylates histone 3 on lysine 4 and 36. Its normal expression is restricted to germ cells and attenuation of its activity results in altered meiotic gene transcription, impairment of double-stranded breaks and pairing between homologous chromosomes. There is growing evidence for a role of aberrant expression of PRDM9 in oncogenesis and genome instability. Here we report the discovery of MRK-740, a potent (IC50: 80 ± 16 nM), selective and cell-active PRDM9 inhibitor (Chemical Probe). MRK-740 binds in the substrate-binding pocket, with unusually extensive interactions with the cofactor S-adenosylmethionine (SAM), conferring SAM-dependent substrate-competitive inhibition. In cells, MRK-740 specifically and directly inhibits H3K4 methylation at endogenous PRDM9 target loci, whereas the closely related inactive control compound, MRK-740-NC, does not. The discovery of MRK-740 as a chemical probe for the PRDM subfamily of methyltransferases highlights the potential for exploiting SAM in targeting SAM-dependent methyltransferases.

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