Structure-activity relationship studies of Imidazo[1',2':1,6]pyrido[2,3-d]pyrimidine derivatives to develop selective FGFR inhibitors as anticancer agents for FGF19-overexpressed hepatocellular carcinoma

  • Eur J Med Chem. 2025 Jan 15:282:117047. doi: 10.1016/j.ejmech.2024.117047.
Jisook Kim  1 ,  Seung Hyun Jung  2 ,  Joo Chan Lee  3 ,  Won Jeoung Kim  2 ,  Jooyun Byun  2 ,  Young Gil Ahn  2 ,  Hyun-Ju Park  4
Affiliations
  • 1. School of Pharmacy, Sungkyunkwan University, Suwon, 16419, South Korea; Department of Drug Discovery, Hanmi Research Center, Hanmi Pharm. Co. Ltd., Gyeonggi-do, 18469, South Korea.
  • 2. Department of Drug Discovery, Hanmi Research Center, Hanmi Pharm. Co. Ltd., Gyeonggi-do, 18469, South Korea.
  • 3. School of Pharmacy, Sungkyunkwan University, Suwon, 16419, South Korea.
  • 4. School of Pharmacy, Sungkyunkwan University, Suwon, 16419, South Korea. Electronic address: [email protected].
PMID: 39566244 DOI: 10.1016/j.ejmech.2024.117047
Abstract

The aberrant activation of Fibroblast Growth Factor (FGF) and FGF receptor (FGFR)-mediated signaling pathways are associated with Cancer development, including hepatocellular carcinoma (HCC). A novel series of imidazo[1',2':1,6]pyrido[2,3-d]pyrimidine, containing an acrylamide covalent warhead, were synthesized as selective FGFR 1-4 inhibitors. Compound 7n was identified as the most potent inhibitor against FGFR1, 2, and 4, with IC50 values of 8/4 nM (FGFR1/2) and 3.8 nM (FGFR4), and the covalent docking analyses suggested that 7n form a covalent adduct with cysteine residue on the hinge or p-loop of FGFR. Compound 7n exhibited a favorable pharmacokinetic profile and significant in vivo antitumor efficacy in human liver Cancer xenograft mouse models (xenograft, FGF/FGFR-dependent HCC cells).

Keywords
Fibroblast growth factor receptor (FGFR); Hepatocellular carcinoma (HCC); Imidazo[1′,2′:1,6]pyrido[2,3-d]pyrimidine.
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