Design and synthesis of CDK9/EZH2 dual-target inhibitors to achieve synergistic antitumor effects

Cyclin-dependent kinase 9 (CDK9) plays a pivotal role in regulating transcriptional elongation and has emerged as a promising target in cancer therapy. However, it is reported that CDK9 inhibitors cause abnormal upregulation of H3K27me3 in Diffuse Large B-cell Lymphoma (DLBCL) cell lines. Here, we designed a series of dual inhibitors targeting CDK9 and EZH2 by linking two distinct pharmacophores to achieve synergistic antitumor effects. Among these, the potent CDK9/EZH2 inhibitor D16 exhibited impressive inhibitory activities, with IC₅₀ values of 83.9 nM for CDK9 and 108.6 nM for EZH2. Notably, compound D16 induced more significant DNA damage and exhibited greater inhibition of DLBCL proliferation than the single-target inhibitor SNS-032 or C24. In addition, D16 showed potent anti-proliferative activities in various solid tumor cell lines, which may provide an innovative strategy for the treatment of cancer.