Discovery of a Potent and Selective Coactivator Associated Arginine Methyltransferase 1 (CARM1) Inhibitor by Virtual Screening

Protein
arginine methyltransferases (PRMTs) represent an emerging
target class in oncology and other disease areas. So far, the most
successful strategy to identify PRMT inhibitors has been to screen
large to medium-size chemical libraries. Attempts to develop PRMT
inhibitors using receptor-based computational methods have met limited
success. Here, using virtual screening approaches, we identify 11
CARM1 (PRMT4) inhibitors with ligand efficiencies ranging from 0.28
to 0.84. CARM1 selective hits were further validated by orthogonal
methods. Two structure-based rounds of optimization produced 27 (SGC2085), a CARM1 inhibitor with an IC50 of
50 nM and more than hundred-fold selectivity over other PRMTs. These
results indicate that virtual screening strategies can be successfully
applied to Rossmann-fold protein methyltransferases.