GLPG1690(Ziritaxestat) is a novel autotaxin (ATX) inhibitor with an IC50 of 131 nM and a Ki of 15 nM. It effectively halts the progression of idiopathic pulmonary fibrosis [1-2].
GLPG1690 (20 nM; 68-96h) inhibits the proliferation of TSC2-deficient cells where ATX is upregulated. Additionally, GLPG1690 suppresses the migration and anchorage-independent growth of TSC2-deficient cells[3].
GLPG1690(i.g; 50 or 100 mg/kg; every 12 hours for 19 days) reduces plasma ATX activity and lysophosphatidic acid (LPA) concentration in mice. Furthermore, GLPG1690 enhances the inhibition of cancer cell proliferation in vivo when combined with irradiation[4]. GLPG1690 reverses lysophosphatidylcholine (LPC)-induced endothelial dysfunction in mice[5].
References:
[1]. Desroy N, Housseman C, et,al. Discovery of 2-[[2-Ethyl-6-[4-[2-(3-hydroxyazetidin-1-yl)-2-oxoethyl]piperazin-1-yl]-8-methylimidazo[1,2-a]pyridin-3-yl]methylamino]-4-(4-fluorophenyl)thiazole-5-carbonitrile (GLPG1690), a First-in-Class Autotaxin Inhibitor Undergoing Clinical Evaluation for the Treatment of Idiopathic Pulmonary Fibrosis. J Med Chem. 2017 May 11;60(9):3580-3590. doi: 10.1021/acs.jmedchem.7b00032. Epub 2017 May 1. PMID: 28414242.
[2]. Maher TM, van der Aar EM, et,al. Safety, tolerability, pharmacokinetics, and pharmacodynamics of GLPG1690, a novel autotaxin inhibitor, to treat idiopathic pulmonary fibrosis (FLORA): a phase 2a randomised placebo-controlled trial. Lancet Respir Med. 2018 Aug;6(8):627-635. doi: 10.1016/S2213-2600(18)30181-4. Epub 2018 May 20. PMID: 29792287.
[3]. Feng Y, Mischler WJ, et,al. Therapeutic Targeting of the Secreted Lysophospholipase D Autotaxin Suppresses Tuberous Sclerosis Complex-Associated Tumorigenesis. Cancer Res. 2020 Jul 1;80(13):2751-2763. doi: 10.1158/0008-5472.CAN-19-2884. Epub 2020 May 11. PMID: 32393662; PMCID: PMC7335343.
[4]. Tang X, Wuest M, et,al. Inhibition of Autotaxin with GLPG1690 Increases the Efficacy of Radiotherapy and Chemotherapy in a Mouse Model of Breast Cancer. Mol Cancer Ther. 2020 Jan;19(1):63-74. doi: 10.1158/1535-7163.MCT-19-0386. Epub 2019 Sep 23. PMID: 31548293.
[5]. Janovicz A, Majer A, et,al. Autotaxin-lysophosphatidic acid receptor 5 axis evokes endothelial dysfunction via reactive oxygen species signaling. Exp Biol Med (Maywood). 2023 Oct;248(20):1887-1894. doi: 10.1177/15353702231199081. Epub 2023 Oct 14. PMID: 37837357; PMCID: PMC10792427.
GLPG1690(Ziritaxestat)是一种新型的autotaxin (ATX)抑制剂，IC50为131 nM, Ki为15 nM。它能有效阻止特发性肺纤维化的进展[1-2]。
GLPG1690(20 nM;68-96h)抑制ATX上调的TSC2缺陷细胞的增殖。此外，GLPG1690还能抑制TSC2缺陷细胞的迁移和不依赖锚定的生长[3]。
GLPG1690 (i.g; 50 or 100 mg/kg; every 12 hours for 19 days) 降低小鼠血浆ATX活性和溶血磷脂酸(LPA)浓度。此外，GLPG1690在体内与辐照联合使用时，可增强对癌细胞增殖的抑制作用[4]。GLPG1690逆转溶血磷脂酰胆碱(LPC)诱导的小鼠内皮功能障碍[5]。