Fibroblast growth factor receptor 2 (FGFR2) represents an appealing therapeutic target for multiple cancers, yet no selective FGFR2 inhibitors have been approved for clinical use to date. Here, we report the discovery of a series of new selective, irreversible FGFR2 inhibitors. The representative compound LHQ490 potently inhibited FGFR2 kinase activity with an IC₅₀ of 5.2 nM, and was >61-, >34-, and >293-fold selective against FGFR1, FGFR3, and FGFR4, respectively. LHQ490 also exhibited high selectivity in a panel of 416 kinases. Cell-based studies revealed that LHQ490 efficiently suppressed the proliferation of BaF3-FGFR2 cells with an IC₅₀ value of 1.4 nM, and displayed >70- and >714-fold selectivity against BaF3-FGFR1 and the parental BaF3 cells, respectively. More importantly, LHQ490 potently suppressed the FGFR2 signaling pathways, selectively inhibited FGFR2-driven cancer cell proliferation, and induced apoptosis of FGFR2-driven cancer cells. Taken together, this study provides a potent and highly selective FGFR2 inhibitor for further development of FGFR2-targeted therapeutic agents.

Turkish neurosurgery4区 · 医学

Effect of Intrathecal Anti-Fibroblast Growth Factor-2 Antibodies on the Mechanical Allodynia and Activation of Spinal Cord Astrocytes in Rats.

4区 · 医学

Article

作者: You, Jiyue ; Chen, Ping ; Gao, Jin

AIMTo investigate the effect of intrathecal anti-fibroblast growth factor-2 (FGF-2) antibodies on the mechanical allodynia and activation of spinal cord astrocytes in a rat model of neuropathic pain.MATERIAL AND METHODSForty male Sprague-Dawley rats were randomly divided into 4 groups (Each group=10 rats). Group A: Spared nerve injury (SNI) model and intrathecal phosphate-buffered saline (PBS); Group B: SNI model and intrathecal FGF-2 antibodies; Group C: Sham surgery and intrathecal PBS; Group D: Sham surgery and intrathecal basic FGF-2 antibodies. The paw withdrawal mechanical threshold (PWMT) was evaluated one day before the operation and at the 1, 4, 7, 14 and 21 days after the operation. Meanwhile, the expression of FGF-2, glial fibrillary acidic protein (GFAP) of astrocytes, tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in the L4~6 spinal cord segments were gauged at 21 days after the operation.RESULTSSNI significantly induced the mechanical allodynia and markedly increased the number of FGF-2 and GFAP positive cells and the levels of TNF-α and IL-6 (p < 0.05). Intrathecal injection of FGF-2 antibodies suppressed the increase of FGF-2 and GFAP positive cells, and the levels of TNF-α and IL-6. These antibodies significantly attenuated SNI-induced mechanical allodynia in rats (p < 0.05).CONCLUSIONFGF-2 antibodies have the effect of analgesia on neuropathic pain in rats.

100 项与 Fibroblast growth factor-2 (Neurobiological Technologies) 相关的药物交易

登录后查看更多信息