Development of (2-(Benzyloxy)phenyl)methanamine Derivatives as Potent and Selective Inhibitors of CARM1 for the Treatment of Melanoma

Coactivator-associated arginine methyltransferase 1 (CARM1),
an
important member of type I protein arginine methyltransferases (PRMTs),
has emerged as a promising therapeutic target for various cancer types.
In our previous study, we have identified a series of type I PRMT
inhibitors, among which ZL-28-6 (6) exhibited increased
activity against CARM1 while displaying decreased potency against
other type I PRMTs. In this work, we conducted chemical modifications
on compound 6, resulting in a series of (2-(benzyloxy)phenyl)methanamine
derivatives as potent inhibitors of CARM1. Among them, compound 17e displayed remarkable potency and selectivity for CARM1
(IC50 = 2 ± 1 nM), along with notable antiproliferative
effects against melanoma cell lines. Cellular thermal shift assay
and western blot experiments confirmed that compound 6 effectively targets CARM1 within cells. Furthermore, compound 17e displayed good antitumor efficacy in a melanoma xenograft
model, indicating that this compound warrants further investigation
as a potential anticancer agent.