Design, synthesis and biological evaluation of novel CDK8/BRD4 dual inhibitors

CDK8 is recognized as an important therapeutic target in colorectal Cancer. Recently, a study has demonstrated that inhibition of CDK8 alone can activate a compensatory BRD4 signaling pathway, which may account for the modest in vivo efficacy of CDK8 small-molecule inhibitors and limits their clinical application in colorectal Cancer treatment. Simultaneously inhibition of CDK8 and BRD4 has been shown to effectively suppress the growth of colorectal Cancer cells, with confirmed safety and efficacy. Nevertheless, to date, no dual-target inhibitors of CDK8/BRD4 have been reported. In this study, a series of 12 novel small-molecule CDK8/BRD4 dual inhibitors were designed and synthesized using a fragment merging strategy. Among these, compound 8d exhibited good inhibitory activity against both CDK8 (IC₅₀ = 5.44 ± 0.10 μM) and BRD4 (IC₅₀ = 4.03 ± 0.95 μM), along with promising anti-proliferative activity in colorectal Cancer cells (HCT116, IC₅₀ = 12.41 ± 0.96 μM). Furthermore, molecular docking analysis elucidated the binding mode of compound 8d with the target proteins, providing valuable insights for the future development of novel CDK8/BRD4 dual inhibitors.