2. Academic Validation
  3. Design and Synthesis of Fibroblast Growth Factor Receptor (FGFR) and Histone Deacetylase (HDAC) Dual Inhibitors for the Treatment of Cancer

Design and Synthesis of Fibroblast Growth Factor Receptor (FGFR) and Histone Deacetylase (HDAC) Dual Inhibitors for the Treatment of Cancer

  • J Med Chem. 2022 Dec 22;65(24):16541-16569. doi: 10.1021/acs.jmedchem.2c01413.
Guoquan Wan 1,  Zhanzhan Feng 1,  Qiangsheng Zhang 1,  Xiao Li 1,  Kai Ran 2,  Huan Feng 1,  Tianwen Luo 1,  Shuyan Zhou 1,  Chang Su 1,  Wei Wei 1,  Ningyu Wang 3,  Chao Gao 4,  Lifeng Zhao 5,  Luoting Yu 1
Affiliations

Affiliations

  • 1 State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu 610041, China.
  • 2 College of Pharmacy, National & Local Joint Engineering Research Center of Targeted and Innovative Therapeutics, Chongqing Key Laboratory of Kinase Modulators as Innovative Medicine, Chongqing University of Arts and Sciences, Chongqing 402160, China.
  • 3 School of Life Science and Engineering, Southwest Jiaotong University, Chengdu 610031, China.
  • 4 Institute of Immunology and Inflammation,Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China.
  • 5 Key Laboratory of Medicinal and Edible Plants Resources Development of Sichuan Education Department, Sichuan Industrial Institute of Antibiotics, School of Pharmacy, Chengdu University, Chengdu 610106, China.
PMID: 36449947 DOI: 10.1021/acs.jmedchem.2c01413
Abstract

The activation of the STAT signal after incubation with the HDAC Inhibitor represents a key mechanism causing resistance to HDAC inhibitors in some solid tumor cells, while the FGFR Inhibitor could downregulate the level of pSTAT3. Inspired by the therapeutic prospect of FGFR/HDAC dual inhibitors, we designed and synthesized a series of quinoxalinopyrazole hydroxamate derivatives as FGFR/HDAC dual inhibitors. Among them, compound 10e potently inhibited FGFR1-4 and HDAC1/2/6/8 and presented improved antiproliferative effects of tumor cells. Further studies indicated that 10e also downregulated the expression of pSTAT3, potentially overcoming resistance to HDAC inhibitors. What's more, 10e significantly inhibited the tumor growth in HCT116 and SNU-16 xenograft models with favorable pharmacokinetic profiles. Collectively, these results supported that 10e could be a new drug candidate for malignant tumors.

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