Discovery of a chemical probe for PRDM9
(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.
(Less)
- author
- publishing date
- 2019-12-17
- 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}}, }