FR900359 is an inhibitor of G proteins Gαq, Gα11, and Gα14 with IC50 values of 13.18, 10.47, and 10nM, respectively and is isolated from the leaves of the ornamental plant Ardisia crenata[1][2]. FR900359 has shown significant therapeutic potential in various disease models, including cancer, cardiovascular diseases, asthma and pulmonary arterial hypertension[3][4][5].
In vitro, FR900359 (0.01, 0.1, 1.0 and 10µM) incubated melanoma cell B16 for 72h reduced cell growth in a concentration-dependent manner without causing direct cytotoxicity but by arresting cell cycle in the G1 phase[2]. FR900359 (100nM, 300nM, 1μM) treated uveal melanoma cells for 1-4 days inhibited cancer cell growth by inhibiting Gαq and downregulating proteins involved in cell cycle and cell proliferation[3]. FR900359 (50nM) treated human patelets for 5min abolished platelet aggregation and secretion induced by lower concentration of the agonists as well. FR900359 treatment with higher concentrations (100nM) for 5min is required to cause a complete inhibition when used with murine platelets[4].
In vivo, FR900359 applied intratracheally (0.1mg/ml, 50μl) before each application of house dust mite allergen on mouse model of asthma prevented increase in collagen deposition and airway hyperresponsiveness[5]. FR900359 (2.5µg/mouse) or DMSO was applied to the lung via the intra-tracheal (i.t.) route 1h before hemodynamic measurements in mice with chronic hypoxia(Hx)-induced pulmonary hypertension (PH). FR900359 application reduced elevated basal right ventricular systolic pressure and slightly attenuated basal heart rate in Hx-induced PH mouse model[6].
References:
[1]Fujioka, M, Koda S, Morimoto Y. Structure of FR900359, a cyclic depsipeptide from Ardisia crenata sims J. Org. Chem. 1988, 53 (12), 2820−2825.
[2] Schrage R, Schmitz L A, Gaffal E et.al. The experimental power of FR900359 to study Gq-regulated biological processes. Nat Commun. 2015 Dec 14;6:10156
[3] Lapadula D, Farias E, Randolph E C, et al. Effects of Oncogenic Gαq and Gα11 Inhibition by FR900359 in Uveal Melanoma. Mol Cancer Res. 2019 Apr;17(4):963-973.
[4] Inamdar V, Patel A, Bhanu Kanth Manne B K, et al. Characterization of UBO-QIC as a Gαq inhibitor in platelets.Platelets. 2015;26(8):771-8
[5] Matthey M, Roberts R, Seidinger A, et al.Targeted inhibition of Gq signaling induces airway relaxation in mouse models of asthma. Sci Transl Med. 2017 Sep 13;9(407):eaag2288.
[6] Seidinger A, Roberts R, Bai Y, et al. Pharmacological Gq inhibition induces strong pulmonary vasorelaxation and reverses pulmonary hypertension. EMBO Mol Med. 2024 Aug;16(8):1930-1956.
FR900359是从观赏植物紫金牛（Ardisia crenata）的叶子中分离得到的G蛋白Gαq、Gα11和Gα14抑制剂，IC50值分别为13.18、10.47和10nM[1][2]。FR900359在多种疾病模型中显示出显著的治疗潜力，包括癌症、心血管疾病、哮喘和肺动脉高压[3][4][5]。
在体外，FR900359（0.01、0.1、1.0和10µM）孵育B16黑色素瘤细胞72小时以浓度依赖的方式抑制细胞生长，增殖抑制功能并非来源于细胞毒性，而是通过使细胞周期停滞于G1期来实现[2]。FR900359（100nM、300nM、1μM）处理葡萄膜黑色素瘤细胞1 - 4天，通过抑制Gαq并下调与细胞周期和细胞增殖有关的蛋白来抑制癌细胞生长[3]。FR900359（50nM）处理人血小板5min可消除低浓度激动剂诱导的血小板聚集和分泌。使用较高浓度（100nM）的FR900359处理5分钟时才能完全抑制小鼠血小板聚集[4]。
在体内，对于哮喘小鼠模型，在每次应用屋尘螨过敏原致敏之前经气管内给予FR900359（0.1mg/ml，50µl），可防止胶原蛋白沉积增加和气道高反应性的出现[5]。FR900359（2.5μg/只）或DMSO通过气管内（i.t.）途径在慢性缺氧（Hx）诱导的肺动脉高压（PH）小鼠进行血流动力学测量前1小时应用于肺部。FR900359的应用降低了Hx诱导的PH小鼠模型中升高的基础右心室收缩压，并轻微减轻了基础心率[6]。