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
  • 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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