2. Academic Validation
  3. Synthesis and biological evaluation of 6-(pyrimidin-4-yl)-1H-pyrazolo[4,3-b]pyridine derivatives as novel dual FLT3/CDK4 inhibitors

Synthesis and biological evaluation of 6-(pyrimidin-4-yl)-1H-pyrazolo[4,3-b]pyridine derivatives as novel dual FLT3/CDK4 inhibitors

  • Bioorg Chem. 2022 Apr;121:105669. doi: 10.1016/j.bioorg.2022.105669.
Xiandeng Li 1,  Tao Yang 2,  Mengshi Hu 2,  Yingxue Yang 2,  Minghai Tang 2,  Dexin Deng 2,  Kongjun Liu 2,  Suhong Fu 2,  Yan Tan 3,  Huan Wang 3,  Yong Chen 2,  Chufeng Zhang 2,  Yong Guo 2,  Bin Peng 2,  Wenting Si 2,  Zhuang Yang 4,  Lijuan Chen 5
Affiliations

Affiliations

  • 1 State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu 610041, Sichuan, China; School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, Sichuan, China.
  • 2 State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu 610041, Sichuan, China.
  • 3 School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, Sichuan, China.
  • 4 State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu 610041, Sichuan, China. Electronic address: [email protected].
  • 5 State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu 610041, Sichuan, China. Electronic address: [email protected].
PMID: 35180490 DOI: 10.1016/j.bioorg.2022.105669
Abstract

FMS-like tyrosine kinase-3 (FLT3) and cyclin-dependent kinase 4/6 (CDK4/6) inhibitors have been proven to play a significant role in tumor therapy. Herein, based on the previously reported JAK2/FLT3 Inhibitor 18e, we described the synthesis, structure-activity relationship and biological evaluation of a series of unique 6-(pyrimidin-4-yl)-1H-pyrazolo[4,3-b]pyridine derivatives that inhibited FLT3 and CDK4 kinases. The optimized compound 23k exhibited low nanomolar range activities with IC50 values of 11 and 7 nM for FLT3 and CDK4, respectively. In the MV4-11 xenograft tumor model, the tumor growth inhibition rate of 23k dosed at 200 mg/kg was 67%, suggesting that 23k possessed an antitumor therapeutic effect.

Keywords

AML; Antitumor; CDK4; Dual Inhibitor; FLT3.

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