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Merck

Discovery of a chemical probe for PRDM9.

Nature communications (2019-12-19)
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 Schapira, Philipp 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
RESUMEN

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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Sigma-Aldrich
Péptido 3X FLAG®, lyophilized powder
Sigma-Aldrich
Triton X-100, laboratory grade
Sigma-Aldrich
cis-11-Methyl-2-dodecenoic acid, ≥90.0% (HPLC)
Sigma-Aldrich
MRK-740-NC, ≥98% (HPLC)
Sigma-Aldrich
MRK-740, ≥98% (HPLC)