Structure-activity relationship studies of Imidazo[1',2':1,6]pyrido[2,3-d]pyrimidine derivatives to develop selective...

Area of Science:

• Medicinal Chemistry
• Oncology
• Molecular Biology

Background:

• Aberrant activation of fibroblast growth factor (FGF) and FGF receptor (FGFR) signaling pathways is implicated in cancer development, particularly hepatocellular carcinoma (HCC).
• Targeting FGFRs presents a therapeutic strategy for cancers driven by these signaling pathways.

Purpose of the Study:

• To synthesize and evaluate a novel series of imidazo[1',2':1,6]pyrido[2,3-d]pyrimidine derivatives as selective FGFR inhibitors.
• To identify potent inhibitors with potential antitumor activity against HCC.

Main Methods:

• Synthesis of imidazo[1',2':1,6]pyrido[2,3-d]pyrimidine derivatives featuring an acrylamide covalent warhead.
• In vitro kinase inhibition assays to determine IC50 values against FGFR1-4.
• Covalent docking analyses to predict binding interactions.
• Pharmacokinetic profiling and in vivo efficacy studies in human liver cancer xenograft mouse models.

Main Results:

• Compound 7n demonstrated potent inhibition against FGFR1, FGFR2, and FGFR4 with IC50 values in the low nanomolar range (e.g., 8/4 nM for FGFR1/2, 3.8 nM for FGFR4).
• Covalent docking suggested that compound 7n forms a covalent adduct with cysteine residues in FGFR.
• Compound 7n exhibited favorable pharmacokinetics and significant in vivo antitumor efficacy in HCC xenograft models.

Conclusions:

• The novel imidazo[1',2':1,6]pyrido[2,3-d]pyrimidine derivatives, particularly compound 7n, are potent and selective FGFR inhibitors.
• Compound 7n shows promise as a therapeutic agent for hepatocellular carcinoma due to its efficacy and favorable drug-like properties.