Acute myeloid leukemia (AML) is a prevalent hematological tumor associated with a high morbidity and mortality rate. CDK9, functioning as a pivotal transcriptional regulator, facilitates transcriptional elongation through phosphorylation of RNA polymerase II, which further governs the protein levels of Mcl-1 and c-Myc. Therefore, CDK9 has been considered as a promising therapeutic target for AML treatment. Here, we present the design, synthesis, and evaluation of CDK9 inhibitors bearing a flavonoid scaffold. Among them, compound 21a emerged as a highly selective CDK9 inhibitor (IC₅₀ = 6.7 nM), exhibiting over 80-fold selectivity towards most other CDK family members and high kinase selectivity. In Mv4-11 cells, 21a effectively hindered cell proliferation (IC₅₀ = 60 nM) and induced apoptosis by down-regulating Mcl-1 and c-Myc. Notably, 21a demonstrated significant inhibition of tumor growth in the Mv4-11 xenograft tumor model. These findings indicate that compound 21a holds promise as a potential candidate for treating AML.

急性髓系白血病（AML）是一种常见的血液肿瘤，发病率和死亡率很高。CDK9 作为关键转录调节因子，通过 RNA 聚合酶 II 的磷酸化促进转录延伸，进一步控制 Mcl-1 和 c-Myc 的蛋白质水平。因此，CDK9被认为是AML治疗的一个有前景的治疗靶点。在这里，我们介绍了带有类黄酮支架的 CDK9 抑制剂的设计、合成和评估。其中，化合物21a成为一种高选择性CDK9抑制剂（IC ₅₀  = 6.7 nM），对大多数其他CDK家族成员表现出超过80倍的选择性和高激酶选择性。在 Mv4-11 细胞中，21a有效阻碍细胞增殖 (IC ₅₀  = 60 nM)，并通过下调 Mcl-1 和 c-Myc 诱导细胞凋亡。值得注意的是，21a在 Mv4-11 异种移植肿瘤模型中表现出对肿瘤生长的显着抑制作用。这些发现表明化合物21a有希望成为治疗 AML 的潜在候选药物。