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

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.

• Authors: Xiandeng Li, Tao Yang, Mengshi Hu, Yingxue Yang, Minghai Tang, Dexin Deng, Kongjun Liu, Suhong Fu, Yan Tan, Huan Wang, Yong Chen, Chufeng Zhang, Yong Guo, Bin Peng, Wenting Si, Zhuang Yang, Lijuan Chen
• Journal: Bioorganic chemistry (Bioorg Chem) Vol. 121 Pg. 105669 (04 2022) ISSN: 1090-2120 [Electronic] United States
• PMID: 35180490 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2022 Elsevier Inc. All rights reserved.

Chemical References

• Antineoplastic Agents
• Protein Kinase Inhibitors
• Pyridines
• FLT3 protein, human
• fms-Like Tyrosine Kinase 3
• CDK4 protein, human
• Cyclin-Dependent Kinase 4
• pyridine

Topics

• Antineoplastic Agents
• Cell Line, Tumor
• Cell Proliferation
• Cyclin-Dependent Kinase 4
• Humans
• Leukemia, Myeloid, Acute (drug therapy)
• Protein Kinase Inhibitors
• Pyridines
• Structure-Activity Relationship
• fms-Like Tyrosine Kinase 3