Identification Of The First Small Molecule Prmt6 Inhibitor Tool Compound

PRMT6 is a nuclear-localized arginine methyl transferase (RMT) capable of adding omega-N(G)-monomethylarginine and asymmetric omega-N(G),N(G)-dimethylarginine derivatives to histone and other protein substrates containing a GAR motif. PRMT6 can methylate both histone and non-histone substrates and is the only RMT known to methylate the H3R2 mark. This mark can act in opposition to the activating H3K4me3 mark, effectively acting as a transcriptional repressor. PRMT6 overexpression has been reported in several cancer types including melanoma and bladder, lung, and prostate carcinoma suggesting that inhibition of PRMT6 activity might have therapeutic utility. However, until now no small molecule PRMT6 inhibitor has been available to carry out in vitro and in vivo studies. Here we report identification of an aryl pyrazole as the first small molecule PRMT6 inhibitor. This tool compound has an IC50 of 10nM in a PRMT6 biochemical assay and the binding mode has been elucidated through crystallography. The compound inhibited methylation of H3R2 in a dose dependent manner in an engineered model in which PRMT6 was transiently expressed in the A375 cell line. The tool compound showed a half-life (t½) of 8.54 ± 1.43 h after a 1 mg/kg intravenous administration to rats and bioavailability of 65.6 ± 4.3% for a 5 mg/kg subcutaneous dose, enabling its use in further in vitro and in vivo target validation. Citation Format: Allison Drew, Lorna Mitchell, Nathalie Rioux, Kerren Swinger, Scott Ribich, Suzanne Jacques-O9hagan, Trupti Lingaraj, Tim Wigle, Tom Riera, Richard Chesworth, Jesse Smith. Identification of the first small molecule PRMT6 inhibitor tool compound. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5376. doi:10.1158/1538-7445.AM2015-5376