PURPOSE Cyclin-dependent kinase 9 (CDK9) is a transcriptional regulator and potential therapeutic target for many cancers. Multiple nonselective CDK9 inhibitors have progressed clinically but were limited by a narrow therapeutic window. This work describes a novel, potent, and highly selective CDK9 inhibitor, AZD4573. EXPERIMENTAL DESIGN The antitumor activity of AZD4573 was determined across broad cancer cell line panels in vitro as well as cell line- and patient-derived xenograft models in vivo. Multiple approaches, including integrated transcriptomic and proteomic analyses, loss-of-function pathway interrogation, and pharmacologic comparisons, were employed to further understand the major mechanism driving AZD4573 activity and to establish an exposure/effect relationship. RESULTS AZD4573 is a highly selective and potent CDK9 inhibitor. It demonstrated rapid induction of apoptosis and subsequent cell death broadly across hematologic cancer models in vitro, and MCL-1 depletion in a dose- and time-dependent manner was identified as a major mechanism through which AZD4573 induces cell death in tumor cells. This pharmacodynamic (PD) response was also observed in vivo, which led to regressions in both subcutaneous tumor xenografts and disseminated models at tolerated doses both as monotherapy or in combination with venetoclax. This understanding of the mechanism, exposure, and antitumor activity of AZD4573 facilitated development of a robust pharmacokinetic/PD/efficacy model used to inform the clinical trial design. CONCLUSIONS Selective targeting of CDK9 enables the indirect inhibition of MCL-1, providing a therapeutic option for MCL-1-dependent diseases. Accordingly, AZD4573 is currently being evaluated in a phase I clinical trial for patients with hematologic malignancies (clinicaltrials.gov identifier: NCT03263637).See related commentary by Alcon et al., p. 761.

中文翻译：

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AZD4573是一种高度选择性的CDK9抑制剂，可抑制MCL-1并诱导血液癌细胞凋亡。

目的依赖细胞周期蛋白的激酶9（CDK9）是许多癌症的转录调节因子和潜在的治疗靶标。多种非选择性CDK9抑制剂已在临床上取得进展，但受到狭窄的治疗窗口的限制。这项工作描述了一种新型的，高效的，高选择性的CDK9抑制剂AZD4573。实验设计在体外广泛的癌细胞系以及体内细胞系和患者来源的异种移植模型中确定了AZD4573的抗肿瘤活性。多种方法，包括整合的转录组学和蛋白质组学分析，功能丧失途径询问以及药理比较，被用来进一步了解驱动AZD4573活性的主要机制并建立暴露/效应关系。结果AZD4573是一种高度选择性和有效的CDK9抑制剂。它证明了在体外血液癌症模型中广泛广泛地快速诱导凋亡和随后的细胞死亡，并且以剂量和时间依赖性的方式鉴定MCL-1消耗是AZD4573诱导肿瘤细胞死亡的主要机制。还可以在体内观察到这种药效学（PD）反应，无论是单药治疗还是与单用venetoclax结合使用，都能导致皮下肿瘤异种移植和扩散模型的耐受剂量下降。对AZD4573的机理，暴露量和抗肿瘤活性的了解促进了稳健的药代动力学/ PD /功效模型的开发，该模型可用于临床试验设计。结论CDK9的选择性靶向能够间接抑制MCL-1，为MCL-1依赖性疾病提供治疗选择。因此，AZD4573目前正在一项针对血液系统恶性肿瘤患者的I期临床试验中进行评估（clinicaltrials.gov标识符：NCT03263637）。761。