HQ461

HQ461 is a small molecule molecular glue degrader that targets Cyclin K (CCNK) and its associated kinase, Cyclin-dependent kinase 12 (CDK12). By inducing the proteasomal degradation of Cyclin K, HQ461 effectively ablates the CDK12/Cyclin K complex, which is a critical regulator of transcriptional elongation and the DNA damage response. In preclinical models of pancreatic ductal adenocarcinoma (PDAC), HQ461 has been shown to inhibit cell proliferation and induce G1-S phase cell cycle arrest. Furthermore, the degradation of Cyclin K via HQ461 sensitizes pancreatic cancer cells to standard-of-care chemotherapies like gemcitabine and paclitaxel (GemTaxol), as well as PARP inhibitors such as olaparib and niraparib, suggesting its potential as a combination therapy to overcome chemoresistance.