Additionally, we disclose five novel CDK12 inhibitors. These results may accelerate the discovery of novel chemical-class drugs for cancer treatment.

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.

We evaluated PDOs sensitivity to carboplatin, PARPi olaparib, CDK12/CDK13i SR-4835, and the combination of olaparib with SR-4835. PDOs profiling may predict treatment responses in patients with PDAC and provide a rationale for prioritizing therapeutic regimens. Furthermore, a synergistic therapeutic effect between olaparib and SR-4835 seems to be present, which, if confirmed and tolerated, could extend the opportunity of targeted therapy to a greater group of patients, by extending eligibility for PARPi irrespective of BRCA germline mutation status.

Therefore, we suggest that inhibition of CDK13 and HMGA2 simultaneously could be an effective strategy for high HMGA2 expression GC. To detect the expression of both genes simultaneously and individually could be of benefit to predict prognosis for GC.

Consequently, selective CDK12/13 inhibitors constitute powerful research tools as well as promising anti-cancer therapeutics, either alone or in combination therapy. Herein the authors discuss the role of CDK12 and CDK13 in normal and cancer cells, describe their utility as a biomarker and therapeutic target, review the medicinal chemistry optimization of existing CDK12/13 inhibitors and outline strategies for the rational design of CDK12/13 selective inhibitors.