BLU-554は線維芽細胞成長因子受容体4 (FGFR4)の選択性の阻害剤である(IC50 = 5nM)[1]。BLU-554は、FGFR4キナーゼの活性を選択的に阻害し、FGF19-FGFR4経路を遮断し、よって腫瘍細胞の増殖と成長を阻害する[2]。BLU-554は、肝細胞癌の治療によく使われる[3-4]。
MKN-45細胞で、BLU-554 (0.05μM, 0.5μM, 5μM; 48h)は、胃癌細胞株MKN-45の増殖を阻害する[5]。HuH-7とJHH-7細胞で、BLU-554 (0-1250nM；12時間、48時間)は細胞でFGFR4活性を効果的に阻害できる[6]。PC9-4X細胞で、BLU-554 (1μM; 72h)はgefitinibのIC50を減らす[7]。
SW480-ELF4細胞皮下腫瘍マウスモデルで、BLU-554 (10mg/kg；胃内；9週間)とKX2-391の併用は、ELF4媒介のCRC転移を著しく阻害する[8]。Hepa1-6-ETV4異種移植マウスモデルで、BLU-554 (100mg/kg；胃内；9週間)の単独治療は、肺の転移を部分的に減らし、Hepa1-6-ETV4のOSを延ばした[9]。
References:
[1]. Dogan-Topal B, Li W, Schinkel AH, et al. Quantification of FGFR4 inhibitor BLU-554 in mouse plasma and tissue homogenates using liquid chromatography-tandem mass spectrometry. Journal of Chromatography B. 2019 Mar 15; 1110: 116-123.
[2]. Subbiah V, Pal SK. Precision oncology for hepatocellular cancer: Slivering the liver by FGF19–FGFR4–KLB pathway inhibition. Cancer discovery. 2019 Dec 1; 9(12): 1646-1649.
[3]. Kim RD, Sarker D, Meyer T, et al. First-in-human phase I study of fisogatinib (BLU-554) validates aberrant fibroblast growth factor 19 signaling as a driver event in hepatocellular carcinoma. Cancer Discovery. 2019; 9(12): 1696-1707.
[4]. Kim R, Sarker D, Macarulla T, et al. Phase 1 safety and clinical activity of BLU-554 in advanced hepatocellular carcinoma (HCC). Annals of Oncology. 2017 Sep 1; 28: v122.
[5]. Zhang X, Zhang X, Han R, et al. BLU-554, a selective inhibitor of FGFR4, exhibits anti-tumour activity against gastric cancer in vitro. Biochemical and Biophysical Research Communications. 2022 Mar 5; 595: 22-27.
[6]. Tao Z, Cui Y, Xu X, et al. FGFR redundancy limits the efficacy of FGFR4-selective inhibitors in hepatocellular carcinoma. Proceedings of the National Academy of Sciences. 2022 Oct 4; 119(40): e2208844119.
[7]. Liu D, Liu H, Gan J, et al. LY2874455 and abemaciclib reverse FGF3/4/19/CCND1 amplification mediated gefitinib resistance in NSCLC. Frontiers in Pharmacology. 2022 Jun 23; 13: 918317.
[8]. Chen X, Chen J, Feng W, et al. FGF19-mediated ELF4 overexpression promotes colorectal cancer metastasis through transactivating FGFR4 and SRC. Theranostics. 2023 Feb 22; 13(4): 1401.
[9]. Xie M, Lin Z, Ji X, et al. FGF19/FGFR4-mediated elevation of ETV4 facilitates hepatocellular carcinoma metastasis by upregulating PD-L1 and CCL2. Journal of Hepatology. 2023 Jul 1; 79(1): 109-125.