DW14383 is an irreversible pan-FGFR inhibitor that suppresses FGFR-dependent tumor growth in vitro and in vivo
文献类型：期刊论文
| 作者 | Dai, Meng-di1,3; Wang, Yue-liang1; Fan, Jun2,3; Dai, Yang1; Ji, Yin-chun1; Sun, Yi-ming1; Peng, Xia1; Li, Lan-lan1; Wang, Yu-ming2,3; Duan, Wen-hu2,3
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| 刊名 | ACTA PHARMACOLOGICA SINICA
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| 出版日期 | 2020-12-07 |
| 页码 | 9 |
| ISSN号 | 1671-4083 |
| 关键词 | receptor tyrosine kinase FGFR inhibitor DW14383 antitumor activity |
| DOI | 10.1038/s41401-020-00567-3 |
| 通讯作者 | Ai, Jing(jai@simm.ac.cn) |
| 英文摘要 | Fibroblast growth factor receptor (FGFR) is a promising anticancer target. Currently, most FGFR inhibitors lack sufficient selectivity and have nonnegligible activity against kinase insert domain receptor (KDR), limiting their feasibility due to the serious side effects. Notably, compensatory activation occurs among FGFR1-4, suggesting the urgent need to develop selective pan-FGFR1-4 inhibitors. Here, we explored the antitumor activity of DW14383, a novel irreversible FGFR1-4 inhibitor. DW14383 exhibited equivalently high potent inhibition against FGFR1, 2, 3 and 4, with IC50 values of less than 0.3, 1.1, less than 0.3, and 0.5 nmol/L, respectively. It is a selective FGFR inhibitor, exhibiting more than 1100-fold selectivity for FGFR1 over recombinant KDR, making it one of the most selective FGFR inhibitors over KDR described to date. Furthermore, DW14383 significantly inhibited cellular FGFR1-4 signaling, inducing G1/S cell cycle arrest, which in turn antagonized FGFR-dependent tumor cell proliferation. In contrast, DW14383 had no obvious antiproliferative effect against cancer cell lines without FGFR aberration, further confirming its selectivity against FGFR. In representative FGFR-dependent xenograft models, DW14383 oral administration substantially suppressed tumor growth by simultaneously inhibiting tumor proliferation and angiogenesis via inhibiting FGFR signaling. In summary, DW14383 is a promising selective irreversible pan-FGFR inhibitor with pan-tumor spectrum potential in FGFR1-4 aberrant cancers, which has the potential to overcome compensatory activation among FGFR1-4. |
| WOS关键词 | SQUAMOUS-CELL CARCINOMA ; SELECTIVE INHIBITOR ; OVERCOME RESISTANCE ; GENE AMPLIFICATION ; POTENT ; DISCOVERY ; MUTATIONS ; FAMILY ; OPPORTUNITIES ; EXPRESSION |
| 资助项目 | Personalized Medicines --Molecular Signature-based Drug Discovery and Development Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12020000] ; Personalized Medicines --Molecular Signature-based Drug Discovery and Development Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12020103] ; National Natural Science Foundation of China for Innovation Research Group[81821005] ; National Natural Science Foundation of China[81773762] ; Collaborative Innovation Cluster Project of Shanghai Municipal Commission of Health and Family Planning[2020CXJQ02] |
| WOS研究方向 | Chemistry ; Pharmacology & Pharmacy |
| 语种 | 英语 |
| 出版者 | NATURE PUBLISHING GROUP |
| WOS记录号 | WOS:000599037500001 |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/296412]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Ai, Jing |
| 作者单位 | 1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Div Antitumor Pharmacol, Shanghai 201203, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, Shanghai 201203, Peoples R China 3.Univ Chinese Acad Sci, Beijing 100049, Peoples R China |
| 推荐引用方式 GB/T 7714 | Dai, Meng-di,Wang, Yue-liang,Fan, Jun,et al. DW14383 is an irreversible pan-FGFR inhibitor that suppresses FGFR-dependent tumor growth in vitro and in vivo[J]. ACTA PHARMACOLOGICA SINICA,2020:9. |
| APA | Dai, Meng-di.,Wang, Yue-liang.,Fan, Jun.,Dai, Yang.,Ji, Yin-chun.,...&Ai, Jing.(2020).DW14383 is an irreversible pan-FGFR inhibitor that suppresses FGFR-dependent tumor growth in vitro and in vivo.ACTA PHARMACOLOGICA SINICA,9. |
| MLA | Dai, Meng-di,et al."DW14383 is an irreversible pan-FGFR inhibitor that suppresses FGFR-dependent tumor growth in vitro and in vivo".ACTA PHARMACOLOGICA SINICA (2020):9. |
入库方式： OAI收割
来源：上海药物研究所
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