Discovery of the First-in-Class Protein Arginine Methyltransferase 1 PROTAC Degrader

Protein arginine methyltransferase 1 (PRMT1) plays a
critical role
in cancer, yet current PRMT1 modulators lack selectivity and rely
on enzymatic inhibition. Here, we developed first-in-class PRMT1-targeting
PROTAC degrader compound 4, designed based on the pharmacophore
of our previously developed PRMT1 inhibitor. Compound 4 potently induces PRMT1 degradation in a concentration-, time-, and
proteasome-dependent manner and exhibits high selectivity, with no
detectable degradation of other common CRBN substrates and other type
I PRMTs. It also effectively inhibited the growth of multiple cancer
cell lines and exhibited a favorable pharmacokinetic profile. Molecular
modeling suggests that the unique conformation of the PRMT1 dimerization
arm promotes productive ternary complex formation with CRBN, providing
a structural basis for selective PRMT1 degradation. Overall, this
study demonstrates that compound 4 is a first-in-class
PRMT1-targeting PROTAC degrader and highlights its value as a chemical
tool for studying PRMT1 biology and its therapeutic potential in PRMT1-dependent
cancers.