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.
Diverse peanut varieties are widely cultivated in China. However, few studies have investigated the effects of germination on the phenolic profiles and antioxidant activities of specific Chinese peanut cultivars. Therefore, this study was conducted to evaluate the effects of germination on total phenolic content (TPC), total flavonoid content (TFC), antioxidant activity, and phenolic profiles of seven peanut cultivars in China. The TPC, TFC, and antioxidant activities were determined by spectrophotometry, while phenolic profiles were analyzed by using ultra-high performance liquid chromatography coupled with quadrupole/time-of-flight mass spectrometry (UPLC-QTOF-MS). The results found that germination significantly increased TPC, TFC, and antioxidant activity. Antioxidant activity was found to be closely related to TPC in germinated peanut extracts, which indicates that phenolics are the main contributors of antioxidants in germinated peanuts. In addition, germination induced significant changes in polyphenolic profiles. In the analyzed samples, 36 phenolic compounds were identified in which most were flavonoids. Overall, these findings highlight that germinated peanuts can be a good natural source of natural antioxidants for human consumption and functional food development.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.