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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 and Eram, Mohammad S , et al. (2019) In Nature Communications 10(1). p.1-11
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... (More)

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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publishing date
type
Contribution to journal
publication status
published
in
Nature Communications
volume
10
issue
1
article number
5759
pages
1 - 11
publisher
Nature Publishing Group
external identifiers
  • pmid:31848333
  • scopus:85076611478
ISSN
2041-1723
DOI
10.1038/s41467-019-13652-x
language
English
LU publication?
no
id
8621fec2-8a3d-44a0-a36d-0aa0be075f14
date added to LUP
2020-01-02 10:24:08
date last changed
2024-11-14 23:50:18
@article{8621fec2-8a3d-44a0-a36d-0aa0be075f14,
  abstract     = {{<p>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.</p>}},
  author       = {{Allali-Hassani, Abdellah and Szewczyk, Magdalena M and Ivanochko, Danton and Organ, Shawna L and Bok, Jabez and Ho, Jessica Sook Yuin and Gay, Florence P H and Li, Fengling and Blazer, Levi and Eram, Mohammad S and Halabelian, Levon and Dilworth, David and Luciani, Genna M and Lima-Fernandes, Evelyne and Wu, Qin and Loppnau, Peter and Palmer, Nathan and Talib, S Zakiah A and Brown, Peter J and Schapira, Matthieu and Kaldis, Philipp and O'Hagan, Ronan C and Guccione, Ernesto and Barsyte-Lovejoy, Dalia and Arrowsmith, Cheryl H and Sanders, John M and Kattar, Solomon D and Bennett, D Jonathan and Nicholson, Benjamin and Vedadi, Masoud}},
  issn         = {{2041-1723}},
  language     = {{eng}},
  month        = {{12}},
  number       = {{1}},
  pages        = {{1--11}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Communications}},
  title        = {{Discovery of a chemical probe for PRDM9}},
  url          = {{http://dx.doi.org/10.1038/s41467-019-13652-x}},
  doi          = {{10.1038/s41467-019-13652-x}},
  volume       = {{10}},
  year         = {{2019}},
}