iCARM1 (ZINC65534584) is a potent, selective inhibitor of protein arginine methyltransferase CARM1 (PRMT4) with IC50 of 12.3 uM, Biacore Kd of 0.67 uM.
iCARM1 is more active in inhibiting CARM1 enzymatic activity and more potent in suppressing breast cancer cell growth than EZM2302 and TP-064.
iCARM1 specifically inhibited CARM1-mediated histone methylation including H3R17me2a and H3R26me2a in a dose-dependent manner but not other histone arginine methylation markers mediated by other members in the PRMT protein family.
iCARM1 treatment caused the reduction of MMA and ADMA in a dose-dependent manner, but no significant changes of the total levels of histone methylation including H3R17me2a or H3R26me2a in HEK293T cells.
Similar to CARM1 knockdown, iCARM1 suppresses the expression of a large set of oncogenic estrogen/ERα-induced genes in breast cancer cells.
iCARM1 activates the transcription of type I IFN and ISGs.
iCARM1 shows cytotoxicity in ERα-positive cell lines, including MCF7, T47D, and BT474with EC50 of 1.797 ± 0.08, 4.74 ± 0.19, and 2.13 ± 0.33 μM, respectively.
iCARM1 inhibits TNBC cell growth both in vitro and in vivo, exhibits synergistic effects when combined with ERα antagonists.