Design, synthesis and bio-evaluation of 2,5-disubstituted thiazole derivatives for potential treatment of acute myeloid leukemia through targeting CDK9

CDK9 plays a vital role in cellular transcriptional regulation. Hyper-activation of CDK9 leads to the occurrence of various cancers including acute myeloid leukemia, thereby rendering CDK9 an attractive target for cancer treatment. Based on hit compound A4 with 2,5-disubstituted thiazole core identified through the SyntaLinker-Hybrid scheme that shows weak inhibitory activity against both CDK9 and MOLM-13 cells, we designed and synthesized 32 derivatives through structural modification. In vitro anti-proliferative test screened and confirmed that 14 compounds showed highly inhibitory activity against MOLM-13 cells with IC₅₀ values in the micromolar range. Among them, compound 24 displayed the best antiproliferative activity against MOLM-13 cells with an IC₅₀ value of 0.034 μM, which was comparable to the positive drug (BAY1251152, IC₅₀ = 0.031 μM). In vitro kinase inhibition assay results demonstrated that compound 24 had considerable inhibitory activity against CDK9 with an IC₅₀ value of 5.5 nM and a weak inhibitory activity on other CDKs. Further cellular mechanism assays revealed that 24 affected CDK9 signaling pathways, induced cellular apoptosis and arrested cell cycle in the G2/M phase. Finally, further studies of compound 24 about molecular docking, molecular dynamics simulations and ADMET prediction were investigated. Collectively, compound 24 deserves further structural optimization and development for the treatment of acute myeloid leukemia.