Foretinib (GSK1363089)

Foretinib (GSK1363089) is a multi-target receptor tyrosine kinase inhibitor. Foretinib primary targets include c-Met (IC₅₀=0.4nM) and VEGFR2 (IC₅₀=0.9nM)^[1-2]. Foretinib blocks tumor cell proliferation, invasion, and metastasis, and inhibits tumor angiogenesis by simultaneously inhibiting c-Met and VEGFR signaling pathways. Foretinib is commonly used in cancer-related research^[3-4].

In vitro, acute myeloid leukemia cell lines (MV4-11, MOLM13) were treated with Foretinib (0.1–100nM) for 48 hours. Foretinib significantly inhibited the proliferation of FLT3-ITD mutant cells and induced apoptosis, while also suppressing the phosphorylation of FLT3 and its downstream targets STAT5, ERK, and AKT^[5]. Endometrial cancer cell lines (ECC, HEC-1A, HEC-108, TEN) were treated with Foretinib (0.1-100µM) for 48 hours. Foretinib induced p53-dependent apoptosis by inhibiting the autocrine HGF/Met signaling pathway, upregulated PUMA protein expression, and inhibited the phosphorylation of Akt and MDM2^[6].

In vivo, in a MDA-MB-231 triple-negative breast cancer xenograft mouse model, mice were orally administered Foretinib (15 or 50mg/kg/day) starting when tumor volume reached 50mm³, continuously for 18 days. Foretinib significantly inhibited tumor growth, downregulated the expression of p-MET and HGF proteins and mRNA, and did not cause toxicity such as weight loss^[7]. In a streptozotocin-induced diabetic neuropathy mouse model, mice were orally administered Foretinib (30mg/kg/day) starting one week after diabetes induction, continuing for 5 weeks. Foretinib significantly alleviated skin nerve fiber loss but led to adverse effects such as weight loss^[8].

References:
[1] Qian F, Engst S, Yamaguchi K, et al. Inhibition of tumor cell growth, invasion, and metastasis by EXEL-2880 (XL880, GSK1363089), a novel inhibitor of HGF and VEGF receptor tyrosine kinases. Cancer Res. 2009 Oct 15;69(20):8009-16.
[2] Kataoka Y, Mukohara T, Tomioka H, et al. Foretinib (GSK1363089), a multi-kinase inhibitor of MET and VEGFRs, inhibits growth of gastric cancer cell lines by blocking inter-receptor tyrosine kinase networks. Invest New Drugs. 2012 Aug;30(4):1352-60.
[3] Sohn SH, Kim B, Sul HJ, et al. Foretinib Inhibits Cancer Stemness and Gastric Cancer Cell Proliferation by Decreasing CD44 and c-MET Signaling. Onco Targets Ther. 2020 Feb 3;13:1027-1035.
[4] Logan TF. Foretinib (XL880): c-MET inhibitor with activity in papillary renal cell cancer. Curr Oncol Rep. 2013 Apr;15(2):83-90.
[5] Wang P, Zhang Y, Xiang R, et al. Foretinib Is Effective in Acute Myeloid Leukemia by Inhibiting FLT3 and Overcoming Secondary Mutations That Drive Resistance to Quizartinib and Gilteritinib. Cancer Res. 2024 Mar 15;84(6):905-918.
[6] Kogata Y, Tanaka T, Ono YJ, et al. Foretinib (GSK1363089) induces p53-dependent apoptosis in endometrial cancer. Oncotarget. 2018 Apr 27;9(32):22769-22784.
[7] Ji X, Meng X, He Q, et al. Foretinib Is Effective against Triple-Negative Breast Cancer Cells MDA-MB-231 In Vitro and In Vivo by Down-Regulating p-MET/HGF Signaling. Int J Mol Sci. 2023 Jan 1;24(1):757.
[8] Daeschler SC, Zhang J, Gordon T, et al. Foretinib mitigates cutaneous nerve fiber loss in experimental diabetic neuropathy. Sci Rep. 2022 May 19;12(1):8444.

Foretinib (GSK1363089)是一种多靶点受体酪氨酸激酶抑制剂，其主要靶点包括c-Met（IC₅₀=0.4nM）和VEGFR2（IC₅₀=0.9nM）^[1-2]。Foretinib可通过同时抑制c-Met和VEGFR信号通路来阻断肿瘤细胞的增殖、侵袭与转移，并抑制肿瘤血管的生成，Foretinib多用于癌症方面的相关研究^[3-4]。

在体外，Foretinib（0.1-100nM）处理急性髓系白血病细胞系（MV4-11、MOLM13）48小时，Foretinib显著抑制FLT3-ITD突变细胞的增殖并诱导细胞凋亡，同时抑制FLT3及其下游STAT5、ERK和AKT的磷酸化^[5]。Foretinib（0.1-100μM）处理子宫内膜癌细胞系（ECC、HEC-1A、HEC-108、TEN）48小时，Foretinib通过抑制自分泌HGF/Met信号通路诱导p53依赖性凋亡，并上调PUMA蛋白表达，同时抑制Akt和MDM2的磷酸化^[6]。

在体内，在MDA-MB-231三阴性乳腺癌异种移植小鼠模型中，Foretinib（15或50mg/kg/day）口服处理（从肿瘤体积达到50mm³开始，连续18天），Foretinib显著抑制肿瘤生长，并下调p-MET和HGF蛋白及mRNA表达，且Foretinib未引起体重下降等毒性反应^[7]。在链脲佐菌素诱导的糖尿病神经病变小鼠模型中，Foretinib（30mg/kg/day）口服处理（从糖尿病诱导后第1周开始，持续5周），Foretinib显著减轻皮肤神经纤维丢失，但Foretinib导致体重下降等不良反应^[8]。