Article

DW14383 is an irreversible pan-FGFR inhibitor that suppresses FGFR-dependent tumor growth in vitro and in vivo

Authors: Meng-di Dai1,2, Yue-liang Wang1, Jun Fan2,3, Yang Dai1, Yin-chun Ji1, Yi-ming Sun1, Xia Peng1, Lan-lan Li1, Yu-ming Wang2,3, Wen-hu Duan2,3, Jian Ding1, Jing Ai1,2
1 Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
2 University of Chinese Academy of Sciences, Beijing 100049, China
3 Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
Correspondence to: Jing Ai: jai@simm.ac.cn,
DOI: 10.1038/s41401-020-00567-3
Received: 8 May 2020
Accepted: 8 October 2020
Advance online: 7 December 2020

Abstract

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.
Keywords: receptor tyrosine kinase; FGFR inhibitor; DW14383; antitumor activity

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