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

ABSTRACT: 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 addi

SUBMITTER: Wang Y 

PROVIDER: S-EPMC11325196 | biostudies-literature | 2024 Jul

REPOSITORIES: biostudies-literature