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
  • 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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