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Discovery of a Dual PRMT5-PRMT7 Inhibitor.

ABSTRACT: The protein arginine methyltransferases PRMT7 and PRMT5, respectively, monomethylate and symmetrically dimethylate arginine side-chains of proteins involved in diverse cellular mechanisms, including chromatin-mediated control of gene transcription, splicing, and the RAS to ERK transduction cascade. It is believed that PRMT5 and PRMT7 act in conjunction to methylate their substrates, and genetic deletions support the notion that these enzymes derepress cell proliferation and migration in cancer. Using available structures of PRMT5, we designed DS-437, a PRMT5 inhibitor with an IC50 value of 6 ?M against both PRMT5 and PRMT7 that is inactive against 29 other human protein-, DNA-, and RNA-methyltransferases and inhibits symmetrical dimethylation of PRMT5 substrates in cells. This compound behaves as a cofactor competitor and represents a valid scaffold to interrogate the potential of the PRMT5-PRMT7 axis as a target for therapy.

SUBMITTER: Smil D

PROVIDER: S-EPMC4394339 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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Discovery of a Dual PRMT5-PRMT7 Inhibitor.

Smil David D Eram Mohammad S MS Li Fengling F Kennedy Steven S Szewczyk Magdalena M MM Brown Peter J PJ Barsyte-Lovejoy Dalia D Arrowsmith Cheryl H CH Vedadi Masoud M Schapira Matthieu M

ACS medicinal chemistry letters 20150302 4

The protein arginine methyltransferases PRMT7 and PRMT5, respectively, monomethylate and symmetrically dimethylate arginine side-chains of proteins involved in diverse cellular mechanisms, including chromatin-mediated control of gene transcription, splicing, and the RAS to ERK transduction cascade. It is believed that PRMT5 and PRMT7 act in conjunction to methylate their substrates, and genetic deletions support the notion that these enzymes derepress cell proliferation and migration in cancer. ...[more]

PMID: 25893041

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