DDO-2728 (compound 19) is a selective AlkB homologue 5 (ALKBH5) inhibitor with an IC50 of 2.97 μM. DDO-2728 increases the abundance of N6 metladenosine (m6A) modifications, inducing cell apoptosis and cycle arrest. DDO-2728 suppresses tumor growth in the MV4−11 xenograft model with favorable safety profile, shows the potential of targeting ALKBH5 in cancer research.
DDO-2728 (0-40 μM, 48 h) increases m6A metlation levels in the MOLM-13, HEK293and MV4−11 cells over a concentration gradient[1].DDO-2728 (0.01-100 μM, 72 h) inhibits the proliferation of MOLM-13 and MV4−11 cells with IC50s of 0.45 and 1.2 μM respectively, and showes a relatively weak toxicity in HEK293 and HUVECs[1].DDO-2728 (20 μM, 48 h) significantly arrests the cell cycle of MOLM-13 and MV4−11 cells at the G1/M phase[1].DDO-2728 (5, 10 μM, 48 h) concentration-dependently induces cell apoptosis of MV4−11 and MOLM-13 cells[1].DDO-2728 (20 μM, 24 h) decreases the half-lives of TACC3 mRNA in MOLM-13 and MV4−11 cells[1].DDO-2728 (0-10 μM, 48 h) significantly reduces the abundance of TACC3 and c-Myc in MOLM-13 and MV4−11 cells at both mRNA and protein levels[1].1.19Metabolic Stability in Rat and Human Plasma and Liver Microsomes[1]
DDO-2728 (10-40 mg/kg, i.p., daily for 14 d) effectively inhibits tumor growth in MV4−11 xenograft nude mice.[1].1.19Pharmacokinetic Parameters of DDO-2728 in Rats[1]
References:
[1]. Zheng-Yu Jiang, et al. Discovery of Pyrazolo[1,5-a]pyrimidine Derivative as a Novel and Selective ALKBH5 Inhibitor for the Treatment of AML. Journal of Medicinal Chemistry. 2023，Article ASAP.