Cyclin-dependent kinase 9 (CDK9) is a transcriptional regulator and a potential therapeutic target in hematologic malignancies. Selective and transient CDK9 inhibition reduces Mcl-1 expression and induces apoptosis in Mcl-1-dependent tumor cells for survival. Here, we describe our efforts to discover a novel series of 2H-benzo[b][1,4]oxazin-3(4H)-one as CDK9 inhibitors. Compound 32k was identified as a selective CDK9 inhibitor with short pharmacokinetic and physicochemical properties suitable for intravenous administration. Short-term treatment with 32k resulted in a rapid dose-dependent decrease in cellular p-Ser2-RNAPII, Mcl-1 and c-Myc, leading to apoptosis in the MV4-11 cell line. Correspondingly, significant in vivo antitumor efficacy was observed in xenograft models derived from multiple hematological tumors with intermittent 32k dosing. These results provide evidence that selective transient CDK9 inhibitors could be used for the treatment of hematologic malignancies.

细胞周期蛋白依赖性激酶 9 (CDK9) 是一种转录调节因子，也是血液系统恶性肿瘤的潜在治疗靶点。选择性和短暂的 CDK9 抑制可降低 Mcl-1 表达并诱导 Mcl-1 依赖性肿瘤细胞凋亡以维持生存。在这里，我们描述了我们为发现一系列新型 2 H -苯并[ b ][1,4]oxazin-3(4 H )-one 作为 CDK9 抑制剂所做的努力。化合物32k被鉴定为选择性CDK9抑制剂，具有适合静脉内给药的短药代动力学和理化特性。32k短期治疗导致细胞 p-Ser2-RNAPII、Mcl-1 和 c-Myc 快速剂量依赖性下降，导致 MV4-11 细胞系凋亡。相应地，在来自多个血液肿瘤的异种移植模型中间歇性32k给药观察到显着的体内抗肿瘤功效。这些结果提供了选择性瞬时 CDK9 抑制剂可用于治疗血液恶性肿瘤的证据。