A CARM1 inhibitor potently suppresses breast cancer both in vitro and in vivo

CARM1, a member of the protein arginine methyltransferase (PRMT) family, regulates a variety of cellular processes. CARM1 overexpression and/or aberrant activation are tightly linked to cancer development, and it is considered as a promising therapeutic target for cancer diagnosis and therapy. However, the number of specific and potent CARM1 inhibitors is limited to date. We herein discovered a CARM1 inhibitor, iCARM1, showed better specificity and stronger activity towards CARM1 both in vitro and in vivo compared to the known CARM1 inhibitors EZM2302 and TP-064. Similar as CARM1 knockdown, iCARM1 suppressed the expression of oncogenic estrogen/ER-target genes, whereas activated type I interferon (IFN) and IFN-induced genes (ISGs) in breast cancer cells. Consequently, iCARM1 potently suppressed tumor growth in multiple mouse breast tumor models. Based on the gene programs iCARM1-regulated, combination therapy with iCARM1 and endocrine therapy drugs or etoposide exhibited synergetic effects in suppressing breast tumor growth. Taken together, we demonstrated that targeting CARM1 by iCARM1 is effective in suppressing CARM1-regulated gene program and breast cancer development, providing a therapeutic avenue for treating breast cancers in the clinic.