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 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 () and Masoud Vedadi ()
Additional contact information
Abdellah Allali-Hassani: Structural Genomics Consortium, University of Toronto
Magdalena M. Szewczyk: Structural Genomics Consortium, University of Toronto
Danton Ivanochko: Structural Genomics Consortium, University of Toronto
Shawna L. Organ: Structural Genomics Consortium, University of Toronto
Jabez Bok: Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR)
Jessica Sook Yuin Ho: Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR)
Florence P. H. Gay: Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR)
Fengling Li: Structural Genomics Consortium, University of Toronto
Levi Blazer: Structural Genomics Consortium, University of Toronto
Mohammad S. Eram: Structural Genomics Consortium, University of Toronto
Levon Halabelian: Structural Genomics Consortium, University of Toronto
David Dilworth: Structural Genomics Consortium, University of Toronto
Genna M. Luciani: Structural Genomics Consortium, University of Toronto
Evelyne Lima-Fernandes: Structural Genomics Consortium, University of Toronto
Qin Wu: Structural Genomics Consortium, University of Toronto
Peter Loppnau: Structural Genomics Consortium, University of Toronto
Nathan Palmer: Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR)
S. Zakiah A. Talib: Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR)
Peter J. Brown: Structural Genomics Consortium, University of Toronto
Matthieu Schapira: Structural Genomics Consortium, University of Toronto
Philipp Kaldis: Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR)
Ronan C. O’Hagan: Merck & Co., Inc.
Ernesto Guccione: Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR)
Dalia Barsyte-Lovejoy: Structural Genomics Consortium, University of Toronto
Cheryl H. Arrowsmith: Structural Genomics Consortium, University of Toronto
John M. Sanders: Merck & Co., Inc.
Solomon D. Kattar: Merck & Co., Inc.
D. Jonathan Bennett: Merck & Co., Inc.
Benjamin Nicholson: Merck & Co., Inc.
Masoud Vedadi: Structural Genomics Consortium, University of Toronto

Nature Communications, 2019, vol. 10, issue 1, 1-11

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-13652-x

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