Discovery of a chemical probe for PRDM9

• DOI: 10.1038/s41467-019-13652-x
• Publication Date: 2019-12-17T11:02:49Z
• Authors: Abdellah Allali-H...; Magdalena M. Szew...; 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-Fern...; 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-Lov...; Cheryl H. Arrowsmith; John M. Sanders; Solomon D. Kattar; D. Jonathan Bennett; Benjamin Nicholson; Masoud Vedadi
• Keywords: 0301 basic medicine; S-Adenosylmethionine; 0303 health sciences; Science; Q; Histone-Lysine N-Methyltransferase; DNA Methylation; Molecular Dynamics Simulation; Crystallography, X-Ray; Gene; Article; PR Domain; 3. Good health; Histones; Histone; Inhibitory Concentration 50; 03 medical and health sciences; HEK293 Cells; Protein Domains; Molecular Probes; Drug Discovery; Humans; Enzyme Inhibitors

PRDM9 is a PR domain containing protein which trimethylates histone 3 on lysine 4 and 36. Its normal expression restricted to germ cells attenuation of its activity results in altered meiotic gene transcription, impairment double-stranded breaks pairing between homologous chromosomes. There growing evidence for role aberrant oncogenesis genome instability. Here we report the discovery MRK-740, potent (IC50: 80 ± 16 nM), selective cell-active inhibitor (Chemical Probe). MRK-740 binds substrate-binding pocket, with unusually extensive interactions cofactor S-adenosylmethionine (SAM), conferring SAM-dependent substrate-competitive inhibition. In cells, specifically directly inhibits H3K4 methylation at endogenous target loci, whereas closely related inactive control compound, MRK-740-NC, does not. The as chemical probe PRDM subfamily methyltransferases highlights potential exploiting SAM targeting methyltransferases.