2. Academic Validation
  3. Synthesis and optimization of LHQ766: A highly selective FGFR2 inhibitor with improved pharmacokinetics

Synthesis and optimization of LHQ766: A highly selective FGFR2 inhibitor with improved pharmacokinetics

  • Eur J Med Chem. 2025 Dec 15:304:118496. doi: 10.1016/j.ejmech.2025.118496.
Huiqiong Li 1,  Qiuju Xun 1,  Bowen Yang 1,  Yuan Tian 1,  Pinglian Wu 1,  Shaohua Chang 2,  Xiaomei Ren 1,  Zhen Wang 3,  Ke Ding 4,  Dawei Ma 5
Affiliations

Affiliations

  • 1 State Key Laboratory of Chemical Biology and Shanghai Hongkong Joint Laboratory in Chemical Synthesis, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, #345 Lingling Rd., Shanghai, 200032, China.
  • 2 KinoTeck Therapeutics Co., Ltd, 35 Sicheng Road, Tianhe District, Guangzhou City, 510663, China.
  • 3 State Key Laboratory of Chemical Biology and Shanghai Hongkong Joint Laboratory in Chemical Synthesis, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, #345 Lingling Rd., Shanghai, 200032, China. Electronic address: [email protected].
  • 4 State Key Laboratory of Chemical Biology and Shanghai Hongkong Joint Laboratory in Chemical Synthesis, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, #345 Lingling Rd., Shanghai, 200032, China. Electronic address: [email protected].
  • 5 State Key Laboratory of Chemical Biology and Shanghai Hongkong Joint Laboratory in Chemical Synthesis, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, #345 Lingling Rd., Shanghai, 200032, China. Electronic address: [email protected].
PMID: 41418742 DOI: 10.1016/j.ejmech.2025.118496
Abstract

Fibroblast Growth Factor receptor 2 (FGFR2) has gained recognition as a compelling therapeutic target in oncology. We present LHQ766, a novel orally bioavailable FGFR2 Inhibitor demonstrating exceptional potency and selectivity, through optimization of our previously reported FGFR2 Inhibitor 7. The structures and purity of all target compounds were confirmed by 1H NMR, 13C NMR, HRMS and HPLC analyses. Compound LHQ766 exhibited strong enzymatic inhibition (IC50 = 7.3 nM against FGFR2), good kinase selectivity (selective over FGFR1/3/4 and 72 Other tyrosine kinases), and remarkable cellular potency (IC50 = 0.5 nM in BaF3-FGFR2 cells). Mechanistic studies through computational modeling and mass spectrometry revealed LHQ766's covalent binding mode with FGFR2. The compound demonstrated dose-dependent suppression of FGFR2 signaling pathways and selective anti-proliferative effects in FGFR2-driven Cancer models. As a key advancement over lead compound 7, LHQ766 showed substantially optimized pharmacokinetic properties, achieving 35.9 % oral bioavailability in rats. These findings positioned LHQ766 as a promising lead compound for targeted FGFR2 therapy.

Keywords

Antiproliferation; Covalent inhibitor; FGFR2; Oral bioavailability; Selectivity.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-180794
    FGFR2 Inhibitor