DS-437

This compound has not been used in animals. DS-437 exhibits an IC50 of 6 uM in vitro and is a dual inhibitor of PRMT5 and PRMT7. In the original publication, this compound is proposed as a chemical scaffold for the development of potent and cell-active chemical probes to investigate the PRMT5-PRMT7 arginine methylation pathways.

DS-437 is the only dual inhibitor for PRMT5 and PRMT7, and currently the only (documented) SAM-competitive inhibitor of PRMT5. Given the growing importance of both methyltransferases, especially with respect to the symmetric dimethyl arginine mark, DS-437 may add value when used in parallel with other chemical probes in an explorative phenotypic assay. Workman and Collins (http://dx.doi.org/10.1016/j.chembiol.2010.05.013) recommend chemical probes have cellular potency <1-10 μM, while also demonstrating dose-dependent inhibition. DS-437 meets these requirements for PRMT5 (~1 μM) but not for PRMT7 (~18 μM) in a biomarker assay using the SmD3 peptide AGRGRGKAAILKAQVAARGRGRGMGRGN as the substrate. IC50 values of ~ 1 μM and ~18 μM (Hill slope: 1.0 in both cases) were determined for PRMT5-­‐MEP50 and PRMT7, respectively. Selectivity against PRMT4 and PRMT9 and broader off-target profiling (as with Cerep and/or the Psychoactive Drug Screening Program (PDSP)) are not provided but would be helpful to fully interpret results.