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 employed an innovative arsenous warhead modality to develop an orally bioavailable CDK12/CDK13 covalent compound. The dual CDK12/CDK13 inhibitor 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.

No abstract

There is growing interest in covalent targeted inhibitors in drug discovery against previously “undruggable” sites and targets. These molecules typically feature an electrophilic warhead that reacts with nucleophilic groups of protein residues, most notably the thiol group of cysteines. One main challenge in the field is to develop versatile utilizable warheads. Here, we characterize the unique features of novel arsenous warheads for reaction with thiol species in a reversible manner and further demonstrate that organoarsenic probes can be chemically tuned toward specific molecular targets by developing selective and potent inhibitors of pyruvate kinase M2 (PKM2). We show that compound 24 is a covalent and allosteric inhibitor of PKM2 and its orally bioavailable prodrug 25 exerts efficacious inhibition of PKM2-dependent tumor growth in vitro and in vivo. Our results introduce 25 and its derivatives as useful pharmacological tools and provide a general road map for targeting the protein cysteinome using arsenous warheads.

Whether viewed from theoretical hypothesis or historical experience, nationalism and national identity are the two pillars during the process of nation-state building. After the “partition of India”, the nationalist forces of India and Pakistan have also grown stronger. At the same time, it has greatly influenced the national identity of the people of India and Pakistan and has had a profound impact on the process of nation-state building in India and Pakistan.

<div>Abstract<p>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.</p>Significance:<p>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.</p></div>

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

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

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