靶向CDK9的PROTAC分子的设计、合成及活性研究

cute myeloid leukemia (AML), a hematologic malignancy originating from hematopoietic stem cells, accounts for 62% of all leukemia-related deaths and poses a serious threat to human health. Studies have shown that cyclin-dependent kinase 9 (CDK9), as a core kinase regulating transcriptional elongation, exhibits significant overexpression characteristics in AML and various malignancies. Recently, proteolysis targeting chimera (PROTAC) technology has advanced rapidly in cancer treatment, with CDK9-targeting PROTAC molecules being developed for AML therapy. However, their clinical translation has been limited by toxicity concerns and unclear in vivo efficacy. This study aims to design DRB-based PROTACs molecules. DRB is currently one of the most selective CDK9 inhibitors but demonstrates significant toxicity. We designed and synthesized a series of alkyl chain-linked DRB-PROTACs molecules, which demonstrated preliminary activity in in vitro anti-proliferation assays with activity dependent on alkyl chain length. In protein degradation experiments, compound I-5showed moderate CDK9 degradation effects in MOLM13 cells. This research indicates that DRB-PROTAC molecules can enhance the anti-tumor cellular activity of small molecule inhibitors. Further structure-activity relationship studies to screen more potent PROTAC molecules may provide new therapeutic strategies for CDK9-based AML treatment.