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Nat Commun. 2019 Dec 17;10(1):5759. doi: 10.1038/s41467-019-13652-x.

Discovery of a chemical probe for PRDM9.

Author information

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. benjamin.nicholson@merck.com.
11
Structural Genomics Consortium, University of Toronto, Toronto, ON, M5G 1L7, Canada. m.vedadi@utoronto.ca.
12
Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, M5S 1A8, Canada. m.vedadi@utoronto.ca.

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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