Discovery of a chemical probe for PRDM9

Abdellah Allali-Hassani, Magdalena M. Szewczyk, Danton Ivanochko, Shawna L. Organ, Jabez Bok, Jessica Sook Yuin Ho, Florence P.H. Gay, Fengling Li, Levi Blazer, Mohammad S. Eram, Levon Halabelian, David Dilworth, Genna M. Luciani, Evelyne Lima-Fernandes, Qin Wu, Peter Loppnau, Nathan Palmer, S. Zakiah A. Talib, Peter J. Brown, Matthieu SchapiraPhilipp Kaldis, Ronan C. O’Hagan, Ernesto Guccione, Dalia Barsyte-Lovejoy, Cheryl H. Arrowsmith, John M. Sanders, Solomon D. Kattar, D. Jonathan Bennett, Benjamin Nicholson, Masoud Vedadi

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

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.

Original languageEnglish
Article number5759
JournalNature Communications
Volume10
Issue number1
DOIs
StatePublished - 1 Dec 2019

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