Discovery of a First-in-Class Inhibitor of the PRMT5-Substrate Adaptor Interaction.
Discovery of a First-in-Class Inhibitor of the PRMT5-Substrate Adaptor Interaction.
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DOI：
10.1021/acs.jmedchem.1c00507
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发表时间：
2021-08-12
影响因子：
7.3
通讯作者：
Ianari, Alessandra
中科院分区：
文献类型：
--
作者：
McKinney, David C.;McMillan, Brian J.;Ranaghan, Matthew;Moroco, Jamie A.;Brousseau, Merissa;Mullin-Bernstein, Zachary;O'Keefe, Meghan;McCarren, Patrick;Mesleh, Michael F.;Mulvaney, Kathleen M.;Robinson, Foxy;Singh, Ritu;Bajrami, Besnik;Wagner, Florence F.;Hilgraf, Robert;Drysdale, Martin J.;Campbell, Arthur J.;Skepner, Adam;Timm, David E.;Porter, Dale;Kaushik, Virendar K.;Sellers, William R.;Ianari, Alessandra
PRMT5 and its substrate adaptor proteins (SAPs), pICln and Riok1, are synthetic lethal dependencies in MTAP-deleted cancer cells. SAPs share a conserved PRMT5 binding motif (PBM) which mediates binding to a surface of PRMT5 distal to the catalytic site. This interaction is required for methylation of several PRMT5 substrates, including histone and spliceosome complexes. We screened for small molecule inhibitors of the PRMT5-PBM interaction and validated a compound series which binds to the PRMT5-PBM interface and directly inhibits binding of SAPs. Mode of action studies revealed formation of a covalent bond between a halogenated pyridazinone group and cysteine 278 of PRMT5. Optimization of the starting hit produced a lead compound, BRD0639, which engages the target in cells, disrupts PRMT5-RIOK1 complexes, and reduces substrate methylation. BRD0639 is a first-in-class PBM-competitive inhibitor that can support studies of PBM-dependent PRMT5 activities and the development of novel PRMT5 inhibitors that selectively target these functions.
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影响因子：
64.5
作者：
McDonald, E. Robert, III;de Weck, Antoine;Sellers, William R.
通讯作者：
Sellers, William R.
影响因子：
7.3
作者：
Ward, Richard A.;Anderton, Mark J.;Waring, Michael J.
通讯作者：
Waring, Michael J.
影响因子：
3.9
作者：
Shibata, Yoshihiro;Chiba, Masato
通讯作者：
Chiba, Masato
影响因子：
50.3
作者：
Kalev, Peter;Hyer, Marc L.;Marjon, Katya
通讯作者：
Marjon, Katya
DOI：
10.1021/jo4000916
发表时间：
2013-06-07
期刊：
The Journal of organic chemistry
影响因子：
--
作者：
Gerard B;Lee MD 4th;Dandapani S;Duvall JR;Fitzgerald ME;Kesavan S;Lowe JT;Marié JC;Pandya BA;Suh BC;O'Shea MW;Dombrowski M;Hamann D;Lemercier B;Murillo T;Akella LB;Foley MA;Marcaurelle LA
通讯作者：
Marcaurelle LA