Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, China.
Acta Pharmacol Sin. 2019 Jun;40(6):823-832. doi: 10.1038/s41401-018-0191-7. Epub 2018 Nov 28.
The fibroblast growth factor receptors (FGFRs) are increasingly considered attractive targets for therapeutic cancer intervention due to their roles in tumor metastasis and angiogenesis. Here, we identified a new selective FGFR inhibitor, C11, and assessed its antitumor activities. C11 was a selective FGFR1 inhibitor with an IC of 19 nM among a panel of 20 tyrosine kinases. C11 inhibited cell proliferation in various tumors, particularly bladder cancer and breast cancer. C11 also inhibited breast cancer MDA-MB-231 cell migration and invasion via suppression of FGFR1 phosphorylation and its downstream signaling pathway. Suppression of matrix metalloproteinases 2/9 (MMP2/9) was associated with the anti-motility activity of C11. Furthermore, the anti-angiogenesis activity of C11 was verified in endothelial cells and chicken chorioallantoic membranes (CAMs). C11 inhibited the migration and tube formation of HMEC-1 endothelial cells and inhibited angiogenesis in a CAM assay. In sum, C11 is a novel selective FGFR1 inhibitor that exhibits potent activity against breast cancer metastasis and angiogenesis.
成纤维细胞生长因子受体（FGFRs）在肿瘤转移和血管生成中发挥作用，因此越来越被认为是治疗癌症的有吸引力的靶点。在这里，我们鉴定了一种新型选择性 FGFR 抑制剂 C11，并评估了其抗肿瘤活性。C11 是一种选择性 FGFR1 抑制剂，在 20 种酪氨酸激酶的组合中，IC50 为 19 nM。C11 抑制多种肿瘤的细胞增殖，尤其是膀胱癌和乳腺癌。C11 通过抑制 FGFR1 磷酸化及其下游信号通路，还抑制乳腺癌 MDA-MB-231 细胞的迁移和侵袭。基质金属蛋白酶 2/9（MMP2/9）的抑制与 C11 的抗迁移活性有关。此外，C11 的抗血管生成活性在内皮细胞和鸡胚尿囊膜（CAM）中得到了验证。C11 抑制 HMEC-1 内皮细胞的迁移和管形成，并在 CAM 测定中抑制血管生成。总之，C11 是一种新型的选择性 FGFR1 抑制剂，对乳腺癌转移和血管生成具有很强的活性。
