Discovery of a chemical probe for PRDM9

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

doi:10.1038/s41467-019-13652-x

Title: Discovery of a chemical probe for PRDM9

Journal Article · Tue Dec 17 00:00:00 UTC 2019 · Nature Communications

DOI: https://doi.org/10.1038/s41467-019-13652-x · OSTI ID:1624225

Allali-Hassani, Abdellah ^[1]; Szewczyk, Magdalena M. ^[2]; Ivanochko, Danton ^[3]; Organ, Shawna L. ^[2]; Bok, Jabez ^[4];

^[4]; Gay, Florence P. H. ^[4]; Li, Fengling ^[2]; Blazer, Levi ^[2]; Eram, Mohammad S. ^[2];

^[2];

^[2]; Wu, Qin ^[2]; Loppnau, Peter ^[2]; Palmer, Nathan ^[4];

^[4];

^[2];

^[5] more »

Univ. of Toronto, ON (Canada). Structural Genomics Consortium; DOE/OSTI
Univ. of Toronto, ON (Canada). Structural Genomics Consortium
Univ. of Toronto, ON (Canada). Structural Genomics Consortium and Princess Margaret Cancer Centre
Agency for Science, Technology and Research (A*STAR), (Singapore). Inst. of Molecular and Cell Biology (IMCB)
Univ. of Toronto, ON (Canada). Structural Genomics Consortium and Dept. of Pharmacology and Toxicology
Agency for Science, Technology and Research (A*STAR), (Singapore). Inst. of Molecular and Cell Biology (IMCB); National Univ. of Singapore (NUS) (Singapore). Dept. of Biochemistry
Merck & Co, Inc., Kenilworth, NJ (United States)
Agency for Science, Technology and Research (A*STAR), (Singapore). Inst. of Molecular and Cell Biology (IMCB); Icahn School of Medicine at Mount Sinai, New York, NY (United States)
Univ. of Toronto, ON (Canada). Structural Genomics Consortium; Nature Research Center, Vilnius (Luthuania)

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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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: AbbVie; Bayer Pharma AG; Boehringer Ingelheim; Canada Foundation for Innovation (CFI); Eshelman Institute for Innovation; Genome Canada through Ontario Genomics Institute; Innovative Medicines Initiative (EU/EFPIA); Janssen; MSD; Merck KGaA; Natural Sciences and Engineering Research Council of Canada (NSERC); Novartis Pharma AG; Ontario Ministry of Research, Innovation and Science (MRIS); Pfizer; São Paulo Research Foundation (FAPESP); Takeda; USDOE Office of Science (SC); Wellcome

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 1624225

Journal Information:: Nature Communications, Journal Name: Nature Communications Journal Issue: 1 Vol. 10; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

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Epigenetics of Host–Pathogen Interactions: The Road Ahead and the Road Behind Gómez-Díaz, Elena; Jordà, Mireia; Peinado, Miguel Angel PLoS Pathogens, Vol. 8, Issue 11 https://doi.org/10.1371/journal.ppat.1003007	journal	November 2012
Type I Interferon Induced Epigenetic Regulation of Macrophages Suppresses Innate and Adaptive Immunity in Acute Respiratory Viral Infection Kroetz, Danielle N.; Allen, Ronald M.; Schaller, Matthew A. PLOS Pathogens, Vol. 11, Issue 12 https://doi.org/10.1371/journal.ppat.1005338	journal	December 2015
Vaccinia Virus Protein C6 Inhibits Type I IFN Signalling in the Nucleus and Binds to the Transactivation Domain of STAT2 Stuart, Jennifer H.; Sumner, Rebecca P.; Lu, Yongxu PLOS Pathogens, Vol. 12, Issue 12 https://doi.org/10.1371/journal.ppat.1005955	journal	December 2016
Spring viraemia of carp virus modulates p53 expression using two distinct mechanisms Li, Shun; Lu, Long-Feng; Liu, Shu-Bo PLOS Pathogens, Vol. 15, Issue 3 https://doi.org/10.1371/journal.ppat.1007695	journal	March 2019
Metabolic–epigenetic crosstalk in macrophage activation Baardman, Jeroen; Licht, Iris; de Winther, Menno PJ Epigenomics, Vol. 7, Issue 7 https://doi.org/10.2217/epi.15.71	journal	October 2015
Friends with social benefits: host-microbe interactions as a driver of brain evolution and development? Stilling, Roman M.; Bordenstein, Seth R.; Dinan, Timothy G. Frontiers in Cellular and Infection Microbiology, Vol. 4 https://doi.org/10.3389/fcimb.2014.00147	journal	October 2014
Influenza Virus: A Master Tactician in Innate Immune Evasion and Novel Therapeutic Interventions Hsu, Alan Chen-Yu Frontiers in Immunology, Vol. 9 https://doi.org/10.3389/fimmu.2018.00743	journal	April 2018
Viral tRNA Mimicry from a Biocommunicative Perspective Ariza-Mateos, Ascensión; Gómez, Jordi Frontiers in Microbiology, Vol. 8 https://doi.org/10.3389/fmicb.2017.02395	journal	December 2017
Modulation of Innate Immune Responses by the Influenza A NS1 and PA-X Proteins Nogales, Aitor; Martinez-Sobrido, Luis; Topham, David Viruses, Vol. 10, Issue 12 https://doi.org/10.3390/v10120708	journal	December 2018
Innate Immunity to H5N1 Influenza Viruses in Humans Ramos, Irene; Fernandez-Sesma, Ana Viruses, Vol. 4, Issue 12 https://doi.org/10.3390/v4123363	journal	November 2012
Common Nodes of Virus–Host Interaction Revealed Through an Integrated Network Analysis Bösl, Korbinian; Ianevski, Aleksandr; Than, Thoa T. ETH Zurich https://doi.org/10.3929/ethz-b-000373044	text	January 2019
Disrupting the Code: Epigenetic Dysregulation of Lymphocyte Function during Infectious Disease and Lymphoma Development Di Pietro, Andrea; Good-Jacobson, Kim L. The Journal of Immunology, Vol. 201, Issue 4 https://doi.org/10.4049/jimmunol.1800137	journal	August 2018

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