| RRC ID |
78778
|
| 著者 |
Li C, Dai Y, Kong X, Wang B, Peng X, Wu H, Shen Y, Yang Y, Ji Y, Wang D, Li S, Li X, Shi Y, Geng M, Zheng M, Ai J, Liu H.
|
| タイトル |
Structural Optimization of Fibroblast Growth Factor Receptor Inhibitors for Treating Solid Tumors.
|
| ジャーナル |
J Med Chem
|
| Abstract |
Small-molecule fibroblast growth factor receptor (FGFR) inhibitors have emerged as a promising antitumor therapy. Herein, by further optimizing the lead compound 1 under the guidance of molecular docking, we obtained a series of novel covalent FGFR inhibitors. After careful structure-activity relationship analysis, several compounds were identified to exhibit strong FGFR inhibitory activity and relatively better physicochemical and pharmacokinetic properties compared with those of 1. Among them, 2e potently and selectively inhibited the kinase activity of FGFR1-3 wildtype and high-incidence FGFR2-N549H/K-resistant mutant kinase. Furthermore, it suppressed cellular FGFR signaling, exhibiting considerable antiproliferative activity in FGFR-aberrant cancer cell lines. In addition, the oral administration of 2e in the FGFR1-amplified H1581, FGFR2-amplified NCI-H716, and SNU-16 tumor xenograft models demonstrated potent antitumor efficacy, inducing tumor stasis or even tumor regression.
|
| 巻・号 |
66(5)
|
| ページ |
3226-3249
|
| 公開日 |
2023-3-9
|
| DOI |
10.1021/acs.jmedchem.2c01507
|
| PMID |
36802596
|
| MeSH |
Antineoplastic Agents* / pharmacology
Antineoplastic Agents* / therapeutic use
Cell Line, Tumor
Humans
Molecular Docking Simulation
Protein Kinase Inhibitors / pharmacology
Protein Kinase Inhibitors / therapeutic use
Receptor, Fibroblast Growth Factor, Type 1
Receptor, Fibroblast Growth Factor, Type 2*
Receptors, Fibroblast Growth Factor
Signal Transduction
Xenograft Model Antitumor Assays
|
| リソース情報 |
| ヒト・動物細胞 |
Ba/F3 |
