F5446 (Compound 1) is a selective small molecule inhibitor of SUV39H1 metltransferase. F5446 decreases H3K9me3 deposition at the FAS promoter, increases Fas expression and increases colorectal carcinoma cell sensitivity to FasL-induced apoptosis in vitro. F5446 suppresses human colon tumor xenograft growth in vivo.
F5446 (0-1 μM, 2 days) has an EC50 of 4.96x10-7 M against recombinant human SUV39H1 and induces apoptotic cell death in the SW620 and LS411N cells[1].F5446 (0-250 nM, 3 days) up-regulates tumor cell surface Fas expression and increases FasL- induced apoptosis in SW620 and LS411N cells[1][2].F5446 (100 or 250 nM, 48 h) inhibits SUV39H1 expression and induces human colon tumor cell cycle arrest and apoptosis[2].
IF5446 (10 mg/kg, s.c.,every two days for 14 days) inhibits SUV39H1 and colon tumor growth at least in part through inhibiting H3K9me3 to increase the expression part through inhibiting H3K9me3 to increase the expression level of granzyme B , perforin , Fasl and IFNy in tumor-infiltrating CTLs in the tumor microenvironment in mice bearing MC38 and CT26 tumor[1][2].IF5446 (10 and 20 mg/kg, s.c.,every two days for 14 days) increases T-cell effector expression to suppress colon carcinoma growth[3].
References:
[1]. Chunwan Lu, et al. Small molecule histone metltransferase SUV39H1 inhibitor and uses thereof. US10577371B2. 2018. [2]. Lu C, et al. SUV39H1 regulates human colon carcinoma apoptosis and cell cycle to promote tumor growth. Cancer Lett. 2020 Apr 28;476:87-96.
[3]. Lu C, et al. SUV39H1 Represses the Expression of Cytotoxic T-Lymphocyte Effector Genes to Promote Colon Tumor Immune Evasion. Cancer Immunol Res. 2019 Mar;7(3):414-427.