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Title: Discovery of a chemical probe for PRDM9

Journal Article · · Nature Communications
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  1. Univ. of Toronto, ON (Canada). Structural Genomics Consortium
  2. Univ. of Toronto, ON (Canada). Structural Genomics Consortium and Princess Margaret Cancer Centre
  3. Agency for Science, Technology and Research (A*STAR), (Singapore). Inst. of Molecular and Cell Biology (IMCB)
  4. Univ. of Toronto, ON (Canada). Structural Genomics Consortium and Dept. of Pharmacology and Toxicology
  5. 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
  6. Merck & Co, Inc., Kenilworth, NJ (United States)
  7. 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)
  8. 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
Citation Metrics:
Cited by: 21 works
Citation information provided by
Web of Science

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Drawing on disorder: How viruses use histone mimicry to their advantage journal June 2018
The MIntAct project—IntAct as a common curation platform for 11 molecular interaction databases journal November 2013
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Bacteria-induced susceptibility to Candida albicans super-infection in mice via monocyte methyltransferase Setdb2 journal May 2018
Microbial genes, brain & behaviour - epigenetic regulation of the gut-brain axis: Microbial genes, brain & behaviour journal December 2013
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An Unbiased Genetic Screen Reveals the Polygenic Nature of the Influenza Virus Anti-Interferon Response journal February 2014
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The interaction of ENL with PAF1 mitigates polycomb silencing and facilitates murine leukemogenesis journal February 2018
4sUDRB-seq: measuring genomewide transcriptional elongation rates and initiation frequencies within cells journal January 2014
Systematic identification of Ctr9 regulome in ERα-positive breast cancer journal November 2016
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The Nucleosome Acidic Patch Regulates the H2B K123 Monoubiquitylation Cascade and Transcription Elongation in Saccharomyces cerevisiae journal August 2015
Epigenetics of Host–Pathogen Interactions: The Road Ahead and the Road Behind journal November 2012
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