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

  • Eur J Med Chem. 2023 Nov 5:259:115711. doi: 10.1016/j.ejmech.2023.115711.
Tizhi Wu  1 ,  Bin Yu  1 ,  Weihong Gong  1 ,  Jing Zhang  1 ,  Sixian Yu  1 ,  Yucheng Tian  1 ,  Tengteng Zhao  1 ,  Zhiyu Li  2 ,  Jubo Wang  3 ,  Jinlei Bian  4
Affiliations
  • 1. Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, PR China.
  • 2. Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, PR China. Electronic address: [email protected].
  • 3. Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, PR China. Electronic address: [email protected].
  • 4. Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, PR China. Electronic address: [email protected].
PMID: 37572539 DOI: 10.1016/j.ejmech.2023.115711
Abstract

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 (IC50 = 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 (IC50 = 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.

Keywords
AML; CDK9 inhibitors; Flavonoid derivatives; Transcriptional addiction.
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