Design and synthesis of 7-azaindole derivatives as potent CDK8 inhibitors for the treatment of acute myeloid leukemia†

It is of great significance to design and synthesize novel structural inhibitors with good antitumor activity. In this study, based on rational design, a total of 42 7-azaindole derivatives as novel CDK8 inhibitors were designed and synthesized. All compounds were screened with antitumor activity and compound 6 (1-(3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)phenyl)-3-(m-tolyl)urea) exhibited the best activity, especially in acute myeloid leukemia (GI₅₀ MV4-11 = 1.97 ± 1.24 μM). This compound also exhibited excellent inhibitory activity against CDK8 (IC₅₀ = 51.3 ± 4.6 nM). Further mechanism studies shown that it could inhibit STAT5 phosphorylation and induce cell cycle arrest in the G1 phase, leading to apoptosis in acute myeloid leukemia cells. In addition, acute toxicity at a dose of 1000 mg kg⁻¹ indicated the low toxicity of this compound.