Investigator

Li Tan

Principle Investigator · Shanghai Institute of Organic Chemistry, Interdisciplinary Research Center on Biology and Chemisitry

LTLi Tan
Papers(3)
Therapeutic targeting…Dual Inhibition of CD…Role and the molecula…
Collaborators(10)
Huaijiang XiangLifeng LinYing LiPeiye ShenQinyang HeRongyu ZangShaoqing ZhouTingyan ShiWen DiXiao Zhang
Institutions(6)
Shanghai Institute Of…Fudan UniversityInterdisciplinary Res…Shanghai Cancer Insti…Shanghai Jiao Tong Un…Union Hospital, Tongj…

Papers

Dual Inhibition of CDK12/CDK13 Targets Both Tumor and Immune Cells in Ovarian Cancer

Abstract 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.

47Works
3Papers
22Collaborators
Cell Line, TumorLung NeoplasmsOvarian NeoplasmsAdenocarcinoma of LungParkinson DiseaseNeoplasm ProteinsPyroptosis

Positions

2016–

Principle Investigator

Shanghai Institute of Organic Chemistry · Interdisciplinary Research Center on Biology and Chemisitry