2. Academic Validation
  3. Design, synthesis, and biological evaluation of Ponatinib-based N-Phenylpyrimidine-2-amine derivatives as novel fibroblast growth factor receptor 4 (FGFR4) selective inhibitors

Design, synthesis, and biological evaluation of Ponatinib-based N-Phenylpyrimidine-2-amine derivatives as novel fibroblast growth factor receptor 4 (FGFR4) selective inhibitors

  • Eur J Med Chem. 2025 Feb 15:284:117206. doi: 10.1016/j.ejmech.2024.117206.
Lei Han 1,  Yu Yu 1,  Ping Deng 2,  Shuai Wang 3,  Junchi Hu 3,  Shuang Wang 2,  Jiecheng Zheng 1,  Junhao Jiang 1,  Yongjun Dang 4,  Rui Long 5,  Zongjie Gan 6
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, College of Pharmacy, Chongqing Medical University, Chongqing, 400016, PR China.
  • 2 Department of Medicinal Chemistry, College of Pharmacy, Chongqing Medical University, Chongqing, 400016, PR China; Chongqing Key Laboratory of Quality Control and Safety Evaluation of APIs, Chongqing Medical University, Chongqing, 400016, PR China.
  • 3 Basic Medicine Research and Innovation Center for Novel Target and Therapeutic Intervention, Ministry of Education, College of Pharmacy, Chongqing Medical University, Chongqing, 400016, PR China.
  • 4 Department of Medicinal Chemistry, College of Pharmacy, Chongqing Medical University, Chongqing, 400016, PR China; Basic Medicine Research and Innovation Center for Novel Target and Therapeutic Intervention, Ministry of Education, College of Pharmacy, Chongqing Medical University, Chongqing, 400016, PR China. Electronic address: yjdang@cqmu.edu.cn.
  • 5 Department of Pharmacy, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, PR China. Electronic address: lrzj820@aliyun.com.
  • 6 Department of Medicinal Chemistry, College of Pharmacy, Chongqing Medical University, Chongqing, 400016, PR China; Chongqing Key Laboratory of Quality Control and Safety Evaluation of APIs, Chongqing Medical University, Chongqing, 400016, PR China. Electronic address: gzj@cqmu.edu.cn.
PMID: 39733483 DOI: 10.1016/j.ejmech.2024.117206
Abstract

Fibroblast Growth Factor receptor 4 (FGFR4) has been proven to be a promising target for FGFR-driven HCC therapy. Great efforts have been devoted to the discovery of FGFR4 inhibitors. In this article, a new class of Ponatinib-based N-phenylpyridine-2-amine derivatives was designed and synthesized as covalent and irreversible FGFR4 selective inhibitors through a rational drug design strategy. The representative compound 10f displayed significant FGFR4 inhibition and reasonable selectivity. Meanwhile, compound 10f strongly suppressed the proliferation of FGFR4 dependent HCC cells both in vitro and in vivo by inhibiting the FGFR4 signaling pathway. Moreover, the irreversible binding to Cys552 in FGFR4 of compound 10f was also characterized by LC-MS/MS. These results provide evidence of 10f as a potential lead compound targeting FGFR4 for anti-HCC agent development.

Keywords

Covalent and irreversible inhibitor; FGFR4; Hepatocellular carcinoma; Ponatinib.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-170690
    FGFR4抑制剂
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z