Design and optimization of selective and potent CDK9 inhibitors with flavonoid scaffold for the treatment of acute myeloid leukemia

• Published in: European journal of medicinal chemistry 2023-11, Vol.259, p.115711-115711, Article 115711
• Main Authors: Wu, Tizhi, Yu, Bin, Gong, Weihong, Zhang, Jing, Yu, Sixian, Tian, Yucheng, Zhao, Tengteng, Li, Zhiyu, Wang, Jubo, Bian, Jinlei
• Format: Article
• Language: English
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2023.115711

Acute myeloid leukemia (AML) is a prevalent hematological tumor associated with a high morbidity and mortality rate. CDK9, functioning as a pivotal transcriptional regulator, facilitates transcriptional elongation through phosphorylation of RNA polymerase II, which further governs the protein levels of Mcl-1 and c-Myc. Therefore, CDK9 has been considered as a promising therapeutic target for AML treatment. Here, we present the design, synthesis, and evaluation of CDK9 inhibitors bearing a flavonoid scaffold. Among them, compound 21a emerged as a highly selective CDK9 inhibitor (IC  = 6.7 nM), exhibiting over 80-fold selectivity towards most other CDK family members and high kinase selectivity. In Mv4-11 cells, 21a effectively hindered cell proliferation (IC  = 60 nM) and induced apoptosis by down-regulating Mcl-1 and c-Myc. Notably, 21a demonstrated significant inhibition of tumor growth in the Mv4-11 xenograft tumor model. These findings indicate that compound 21a holds promise as a potential candidate for treating AML.