Discovery of a novel CDK4/6 and HDAC dual-targeting agent for the treatment of hepatocellular carcinoma.

The down-regulation of p21 after long-term CDK4/6 inhibition represents a key mechanism causing resistance to CDK4/6 inhibitors in some tumor cells, while the HDAC inhibitor could upregulate the level of p21. Herein, a series of novel CDK4/6 and HDAC dual-targeting inhibitors based on the moiety of palbociclib were designed and synthesized. Among them, compound N14 potently inhibited CDK4/6 and HDAC1/6 at nanomolar levels and induced cell apoptosis and G/G phase arrest through HDAC-p21-CDK signaling pathway in HuH-7 cell line. And N14 also upregulated the expression of acetyl-H3 and p21. Furthermore, N14 significantly suppresses the proliferation of various HCC cells and the HuH-7 xenograft model without evident toxicity. Our study suggests compound N14 is a novel dual-targeting CDK4/6-HDAC inhibitor that represents a promising treatment strategy for HCC.