Therapeutic perturbation of cyclin-dependent kinase 12 (CDK12) is proposed to have pleiotropic effects in ovarian cancer, including direct cytotoxicity against tumor cells and indirect induction of immunogenicity that confer synthetic sensitivity to immune-based treatment. However, formal testing of this hypothesis has been hindered by an insufficient mechanistic understanding of CDK12 and its close homolog CDK13, as well as generally unfavorable pharmacokinetics of available CDK12/CDK13 covalent inhibitors. In this study, we used an innovative arsenous warhead modality to develop an orally bioavailable CDK12/CDK13 covalent compound. The dual CDK12/CDK13 inhibitors ZSQ836 exerted potent anticancer activity in cell culture and mouse models and induced transcriptional reprogramming, including downregulation of DNA damage response genes. CDK12 and CDK13 were both ubiquitously expressed in primary and metastatic ovarian cancer, and the two kinases performed independent and synergistic functions to promote tumorigenicity. Unexpectedly, although ZSQ836 triggered genomic instability in malignant cells, it counterintuitively impaired lymphocytic infiltration in neoplastic lesions by interfering with T-cell proliferation and activation. These findings highlight the Janus-faced effects of dual CDK12/CDK13 inhibitors by simultaneously suppressing tumor and immune cells, offering valuable insights into the future direction of drug discovery to pharmacologically target CDK12. Significance: This study dissects the specific roles of CDK12 and CDK13 in ovarian cancer and develops a CDK12/CDK13 inhibitor that impairs both tumor and immune cells, which could guide future CDK12 inhibitor development.

中文翻译：

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CDK12/CDK13 的双重抑制作用同时针对卵巢癌中的肿瘤细胞和免疫细胞

细胞周期蛋白依赖性激酶 12 (CDK12) 的治疗扰动被认为对卵巢癌具有多效作用，包括针对肿瘤细胞的直接细胞毒性和间接诱导免疫原性，从而赋予基于免疫的治疗的综合敏感性。然而，由于对 CDK12 及其密切同源物 CDK13 的机制了解不足，以及现有 CDK12/CDK13 共价抑制剂的药代动力学通常不利，这一假设的正式测试受到阻碍。在这项研究中，我们使用创新的砷弹头方式开发了一种口服生物可利用的 CDK12/CDK13 共价化合物。CDK12/CDK13 双重抑制剂 ZSQ836 在细胞培养和小鼠模型中发挥有效的抗癌活性，并诱导转录重编程，包括下调 DNA 损伤反应基因。CDK12和CDK13在原发性和转移性卵巢癌中普遍表达，两种激酶在促进致瘤性方面发挥独立和协同作用。出乎意料的是，虽然 ZSQ836 引发了恶性细胞的基因组不稳定，但它通过干扰 T 细胞增殖和激活，损害了肿瘤病变中的淋巴细胞浸润。这些发现强调了双重 CDK12/CDK13 抑制剂通过同时抑制肿瘤和免疫细胞而产生的两面性效应，为药理学靶向 CDK12 的药物发现的未来方向提供了宝贵的见解。意义：本研究剖析了CDK12和CDK13在卵巢癌中的具体作用，并开发了一种同时损害肿瘤和免疫细胞的CDK12/CDK13抑制剂，