Identification, Synthesis, and Biological Evaluations of Potent Inhibitors Targeting Type I Protein Arginine Methyltransferases

CARM1 (coactivator-associated arginine
methyltransferase 1), which
belongs to type I PRMTs (protein arginine methyltransferases), is
a potential therapeutic target for treatment of multiple cancers.
In this study, we first identified several hit compounds against CARM1
by structure-based virtual screening (IC50 = 35.51 ±
6.68 to 68.70 ± 8.12 μM) and then carried out chemical
structural optimizations, leading to six compounds with significantly
improved activities targeting CARM1 (IC50 = 18 ± 2
to 107 ± 6 nM). As a compound with an ethylenediamino motif,
the most potent inhibitor, ZL-28-6, also exhibited potent inhibition
against other type I PRMTs. Compared to the type I PRMT inhibitor
from our previous work (DCPR049_12), ZL-28-6 showed increased potency
against CARM1 and decreased activity against other type I PRMTs. Moreover,
ZL-28-6 showed better antiproliferation activities toward a series
of solid tumor cells than DCPR049_12, indicating its broad spectrum
of anticancer activity. In addition, cellular thermal shift and Western
blot assays validated that ZL-28-6 could target CARM1 in cells. Taken
together, the inhibitor we identified could serve as a potent probe
for studying CARM1’s biological functions and shed light on
the future design of novel CARM1 inhibitors with stronger activities
and selectivities.