Design and Synthesis of Potent, Selective Inhibitors of Protein Arginine Methyltransferase 4 against Acute Myeloid Leukemia

PRMT4
is a type I protein arginine methyltransferase and plays
important roles in various cellular processes. Overexpression of PRMT4
has been found to be involved in several types of cancers. Selective
and in vivo effective PRMT4 inhibitors are needed for demonstrating
PRMT4 as a promising therapeutic target. On the basis of compound 6, a weak dual PRMT4/6 inhibitor, we constructed a tetrahydroisoquinoline
scaffold through a cut-and-sew scaffold hopping strategy. The subsequent
SAR optimization efforts employed structure-based approach led to
the identification of a novel PRMT4 inhibitor 49. Compound 49 exhibited prominently high potency and selectivity, moderate
pharmacokinetic profiles, and good antitumor efficacy in acute myeloid
leukemia xenograft model via oral administration, thus demonstrating
this compound as a useful pharmacological tool for further target
validation and drug development in cancer therapy.