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

Eur J Med Chem

Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, PR China. Electronic address:

Published: November 2023

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.

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Source
http://dx.doi.org/10.1016/j.ejmech.2023.115711DOI Listing

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