Design and synthesis of 7-azaindole derivatives as potent CDK8 inhibitors for the treatment of acute myeloid leukemia.
Yumeng WangCencen LeiQuan WangXingxing ZhangLiping ZhiXin Hua LiuPublished in: RSC medicinal chemistry (2024)
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-((1 H -pyrrolo[2,3- b ]pyridin-5-yl)oxy)phenyl)-3-( m -tolyl)urea) exhibited the best activity, especially in acute myeloid leukemia (GI 50 MV4-11 = 1.97 ± 1.24 μM). This compound also exhibited excellent inhibitory activity against CDK8 (IC 50 = 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.
Keyphrases
- cell cycle arrest
- cell death
- pi k akt
- cell cycle
- acute myeloid leukemia
- oxidative stress
- cell proliferation
- signaling pathway
- induced apoptosis
- liver failure
- endoplasmic reticulum stress
- photodynamic therapy
- intensive care unit
- acute lymphoblastic leukemia
- drug induced
- smoking cessation
- case control
- mechanical ventilation
- extracorporeal membrane oxygenation