ALKBH5-IN-5

ALKBH5-IN-5 is a highly selective ALKBH5 ( IC₅₀ = 0.62 μM, K d = 804 nM). ALKBH5-IN-5 disrupts ALKBH5 binding to m 6 A-RNA and 6mA-DNA substrates. ALKBH5-IN-5 promotes differentiation, induces apoptosis, cause G2-M phase arrest and exerts strong antiproliferative effects in cancer cells. ALKBH5-IN-5 reduces TACC3 and MYC protein levels and increases cleaved caspase-3 levels. ALKBH5-IN-5 exerts antitumor activity in tumor xenograft mice models. ALKBH5-IN-5 can be used for the research of acute myeloid leukemia ^[1].

In Vivo, ALKBH5-IN-5 (Compound 18l) (1-2.5 mg/kg; i.p.; daily; 14 days) exhibits effective antileukemia activity in female BALB/c nude mice with acute myeloid leukemia (with tumor growth inhibition of 66.3% and 76.8%)^[1].

In Vitro, ALKBH5-IN-5 (Compound 18l) selectively inhibits ALKBH5 (IC₅₀ = 0.62 ± 0.12 μM; Kd = 804 ± 117 nM) and shows minimal FTO inhibition^[1]. ALKBH5-IN-5 disrupts ALKBH5 binding to m6A-RNA and 6mA-DNA substrates^[1]. ALKBH5-IN-5 (20-80 μM) covalently modifies ALKBH5 at C200, C100, and C267, with IC₅₀ of 0.7, 30.34 and 1.15 μM^[1]. ALKBH5-IN-5 (72 h) inhibits proliferation of LM-13, MV4-11, NOMO-1, and NB4 cells (IC₅₀ = 1.92, 1.50, 2.99 and 0.63 μM) and has low cytotoxicity in HEK293 cells^[1]. ALKBH5-IN-5 (25-500 nM) suppresses NB4 cell colony formation, with near elimination at 500 nM^[1]. ALKBH5-IN-5 (2-15 μM; 24-72 h) induces apoptosis, promotes differentiation, and arrests the cell cycle at G2-M phase in NB4 cells^[1]. ALKBH5-IN-5 (5-10 μM; 48 h) reduces TACC3 and MYC protein levels and increases cleaved caspase-3 levels in NB4 cells^[1].

References:
[1]. Wu H, et al. Discovery of Covalent and Cell-Active ALKBH5 Inhibitors with Potent Antileukemia Effects In Vivo. Angew Chem Int Ed Engl. 2025;64(18):e202424928.