2. Academic Validation
  3. Design, synthesis and biological evaluation of novel platelet-derived growth factor receptor-α (PDGFR-α) inhibitors based on 4-anilinoquinoline and 4-anilinoquinazoline scaffolds

Design, synthesis and biological evaluation of novel platelet-derived growth factor receptor-α (PDGFR-α) inhibitors based on 4-anilinoquinoline and 4-anilinoquinazoline scaffolds

  • Eur J Med Chem. 2025 Nov 15:298:118015. doi: 10.1016/j.ejmech.2025.118015.
Ru Wang 1,  Sheng-Xin Yao 1,  Ye-Wei Pang 1,  Yu-Jing Huang 1,  Hai-Yue Lu 2,  Jian Pan 3,  Ying Liu 4,  Ting-Ting Du 5,  Lei Shi 6
Affiliations

Affiliations

  • 1 Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, 210009, China.
  • 2 Bryn Mawr College, Bryn Mawr, PA, 19010, USA.
  • 3 Institute of Pediatric Research, Children's Hospital of Soochow University, Suzhou, 215003, China.
  • 4 Institute of Pediatric Research, Children's Hospital of Soochow University, Suzhou, 215003, China. Electronic address: d201077400@alumni.hust.edu.cn.
  • 5 State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China. Electronic address: ninadu@imm.ac.cn.
  • 6 Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, 210009, China. Electronic address: shilei@cpu.edu.cn.
PMID: 40749254 DOI: 10.1016/j.ejmech.2025.118015
Abstract

Novel 4-anilinoquinoline and 4-anilinoquinazoline hybrids were designed and synthesized as PDGFR-α inhibitors based on lenvatinib, ripretinib and sorafenib. The target compounds were screened in vitro for their anti-PDGFR-α activity. Most of the compounds had shown promising activity in the PDGFR-α kinase assay. Compound 6o (IC50 = 2.1 nM) stood out as the most potent against PDGFR-α. In addition, the target derivatives were assessed for their Anticancer activity against human colon Cancer HT-29 cell. Compound 5p (IC50 = 0.67 μM) and 6o (IC50 = 1.48 μM) were more potent than sorafenib (IC50 = 3.55 μM) against HT-29 cell line. In 76 different kinase selectivity profile study, 5p displayed the highest kinase inhibitory rate to PDGFR-α (98.85 % at 10 μM). In vivo study, the zebrafish model with PDGFR-α labeling also verified that compound 6o outperformed sorafenib in both in vivo anti angiogenic activity and embryonic lethal toxicity. Furthermore, molecular docking results showed that 6o could stably bind to the ATP site of PDGFR-α rationalizing their potent anti-PDGFR-α activity. Based on the above findings, compound 6o could be considered an effective anti-angiogenesis candidate.

Keywords

Anti-Angiogenesis; Colon cancer; Kinase selectivity; Molecular docking; PDGFR-α; Zebrafish.

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