AZD4573 Is a Highly Selective CDK9 Inhibitor That Suppresses MCL-1 and Induces Apoptosis in Hematologic Cancer Cells
AZD4573 Is a Highly Selective CDK9 Inhibitor That Suppresses MCL-1 and Induces Apoptosis in Hematologic Cancer Cells
复制标题
DOI：
10.1158/1078-0432.ccr-19-1853
复制
发表时间：
2020-02-15
影响因子：
11.5
通讯作者：
Drew, Lisa
中科院分区：
文献类型：
--
作者：
Cidado, Justin;Boiko, Scott;Drew, Lisa
目的：细胞周期蛋白依赖性激酶9（Cyclin-dependent kinase 9，CDK 9）是一种转录调节因子，是多种肿瘤的潜在治疗靶点。多种非选择性CDK 9抑制剂已在临床上取得进展，但受到狭窄治疗窗的限制。本研究描述了一种新型、强效、高选择性的CDK 9抑制剂AZD 4573。实验设计：在体外广泛的癌细胞系组以及体内细胞系和患者来源的异种移植模型中测定AZD 4573的抗肿瘤活性。采用多种方法，包括整合转录组学和蛋白质组学分析、功能丧失途径询问和药理学比较，以进一步了解驱动AZD 4573活性的主要机制，并建立暴露/效应关系。在体外血液学癌症模型中，AZD 4573广泛地表现出快速诱导细胞凋亡和随后的细胞死亡，并且以剂量和时间依赖性方式的MCL-1消耗被确定为AZD 4573诱导肿瘤细胞细胞死亡的主要机制。在体内也观察到这种药效学（PD）反应，这导致皮下肿瘤异种移植物和播散模型在耐受剂量下（单药治疗或与维奈托克联合治疗）消退。对AZD 4573的机制、暴露和抗肿瘤活性的理解促进了一个稳健的药代动力学/PD/疗效模型的开发，该模型用于为临床试验design.Conclusions提供信息：选择性靶向CDK 9能够间接抑制MCL-1，为MCL-1依赖性疾病提供治疗选择。因此，AZD 4573目前正在血液恶性肿瘤患者的I期临床试验中进行评估（clinicaltrials.gov标识符：NCT 03263637）。参见Alcon等人的相关评论，第761页
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