Discovery of a chemical probe for PRDM9
- Univ. of Toronto, ON (Canada). Structural Genomics Consortium
- Univ. of Toronto, ON (Canada). Structural Genomics Consortium and Princess Margaret Cancer Centre
- Agency for Science, Technology and Research (A*STAR), (Singapore). Inst. of Molecular and Cell Biology (IMCB)
- Univ. of Toronto, ON (Canada). Structural Genomics Consortium and Dept. of Pharmacology and Toxicology
- Agency for Science, Technology and Research (A*STAR), (Singapore). Inst. of Molecular and Cell Biology (IMCB); National Univ. of Singapore (NUS) (Singapore). Dept. of Biochemistry
- Merck & Co, Inc., Kenilworth, NJ (United States)
- Agency for Science, Technology and Research (A*STAR), (Singapore). Inst. of Molecular and Cell Biology (IMCB); Icahn School of Medicine at Mount Sinai, New York, NY (United States)
- Univ. of Toronto, ON (Canada). Structural Genomics Consortium; Nature Research Center, Vilnius (Luthuania)
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.
- Research Organization:
- Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
- Sponsoring Organization:
- USDOE Office of Science (SC); AbbVie; Bayer Pharma AG; Boehringer Ingelheim; Canada Foundation for Innovation (CFI); Eshelman Institute for Innovation; Genome Canada through Ontario Genomics Institute; Innovative Medicines Initiative (EU/EFPIA); Janssen; Merck KGaA; MSD; Novartis Pharma AG; Ontario Ministry of Research, Innovation and Science (MRIS); Pfizer; São Paulo Research Foundation (FAPESP); Takeda; Wellcome; Natural Sciences and Engineering Research Council of Canada (NSERC)
- Grant/Contract Number:
- AC02-06CH11357; 115766; NMRC/OFIRG/0032/2017; NRF-CRP17-2017-06
- OSTI ID:
- 1624225
- Journal Information:
- Nature Communications, Vol. 10, Issue 1; ISSN 2041-1723
- Publisher:
- Nature Publishing GroupCopyright Statement
- Country of Publication:
- United States
- Language:
- English
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