City of Hope National Medical Center, Duarte, CA, USA.
Leuk Lymphoma. 2023 Dec;64(12):1893-1904. doi: 10.1080/10428194.2023.2244102. Epub 2023 Aug 8.
Cyclin-dependent kinases (CDK) regulate cell cycle and transcriptional activity. Pan-CDK inhibitors demonstrated early efficacy in lymphoid malignancies, but also have been associated with narrow therapeutic index. Among transcriptional CDKs, CDK7 and CDK9 emerged as promising targets. CDK9 serves as a component of P-TEFb elongation complex and thus is indispensable in mRNA transcription. Selective CDK9 inhibitors demonstrated pre-clinical efficacy in and models of B-cell non-Hodgkin lymphoma. CDK9 inhibition results in transcriptional pausing with rapid downmodulation of short-lived oncogenic proteins, e.g. Myc and Mcl-1, followed by cell apoptosis. Early phase clinical trials established safety of CDK9 inhibitors, with manageable neutropenia, infections and gastrointestinal toxicities. In this review, we summarize the rationale of targeting CDK9 in lymphoid malignancies, as well as pre-clinical and early clinical data with pan-CDK and selective CDK9 inhibitors.
细胞周期蛋白依赖性激酶 (CDK) 调节细胞周期和转录活性。泛 CDK 抑制剂在淋巴恶性肿瘤中表现出早期疗效，但也与狭窄的治疗指数相关。在转录 CDK 中，CDK7 和 CDK9 已成为有前途的靶点。CDK9 作为 P-TEFb 延伸复合物的组成部分，因此在 mRNA 转录中不可或缺。选择性 CDK9 抑制剂在 B 细胞非霍奇金淋巴瘤的 和 模型中显示出临床前疗效。CDK9 抑制导致转录暂停，短寿命致癌蛋白（例如 Myc 和 Mcl-1）迅速下调，随后细胞凋亡。早期临床试验确定了 CDK9 抑制剂的安全性，可管理中性粒细胞减少症、感染和胃肠道毒性。在这篇综述中，我们总结了靶向 CDK9 在淋巴恶性肿瘤中的基本原理，以及泛 CDK 和选择性 CDK9 抑制剂的临床前和早期临床数据。
