GRI 977143 is a non-lipid agonist targeting the lysophosphatidic acid receptor 2 (LPA₂) with an EC50 value of 3.3μM[1]. It functions by mimicking the biological activity of the endogenous ligand lysophosphatidic acid (LPA), activating downstream LPA₂ signaling pathways, such as G protein-coupled cascades[2]. This activation subsequently regulates critical cellular processes including proliferation, migration, survival, and inflammatory responses[3].
In vitro, GRI 977143 (10μM) treatment for 24h significantly promoted the growth of LPA₂-transduced mouse embryonic fibroblast (MEF) cells[1]. In non-small cell lung cancer (NSCLC) cells, a 30min treatment with GRI 977143 (1μM) markedly enhanced resistance to cisplatin (CDDP), resulting in a significant increase in cell survival rate[4]. Furthermore, when MEF cells were exposed to 15 Gy γ-irradiation followed by 1h treatment with GRI 977143 (10μM), the compound effectively suppressed Caspase-9 expression and consequently attenuated γ-radiation-induced apoptosis[5].
In vivo, in an ovalbumin (OVA)-induced murine asthma model, a single intraperitoneal administration of GRI 977143 (1mg/kg) 30min prior to OVA sensitization significantly suppressed the elevation of eosinophil and lymphocyte levels[6].Daily intraperitoneal administration of GRI 977143 (3mg/kg) for four consecutive days activates lysophosphatidic acid receptor 2 (LPA₂), thereby ameliorating secretory diarrhea in myosin VB (MYO5B) knockout mice[7].
References:
[1] Kiss GN, Fells JI, Gupte R, Lee SC, Liu J, Nusser N, Lim KG, Ray RM, Lin FT, Parrill AL, Sümegi B, Miller DD, Tigyi G. Virtual screening for LPA2-specific agonists identifies a nonlipid compound with antiapoptotic actions. Mol Pharmacol. 2012 Dec;82(6):1162-73.
[2] Ishimoto K, Minami A, Minami K, Ueda N, Tsujiuchi T. Different effects of lysophosphatidic acid receptor-2 (LPA2) and LPA5 on the regulation of chemoresistance in colon cancer cells. J Recept Signal Transduct Res. 2021 Feb;41(1):93-98.
[3]Takai M, Mori S, Honoki K, Tsujiuchi T. Roles of lysophosphatidic acid (LPA) receptor-mediated signaling in cancer cell biology. J Bioenerg Biomembr. 2024 Aug;56(4):475-482.
[4]Ueda N, Minami K, Ishimoto K, Tsujiuchi T. Effects of lysophosphatidic acid (LPA) receptor-2 (LPA2) and LPA3 on the regulation of chemoresistance to anticancer drug in lung cancer cells. Cell Signal. 2020 May;69:109551.
[5]Kiss GN, Lee SC, Fells JI, Liu J, Valentine WJ, Fujiwara Y, Thompson KE, Yates CR, Sümegi B, Tigyi G. Mitigation of radiation injury by selective stimulation of the LPA(2) receptor. Biochim Biophys Acta. 2013 Jan;1831(1):117-25.
[6]Lee YJ, Im DS. Efficacy Comparison of LPA2 Antagonist H2L5186303 and Agonist GRI977143 on Ovalbumin-Induced Allergic Asthma in BALB/c Mice. Int J Mol Sci. 2022 Aug 28;23(17):9745.
[7]Kaji I, Roland JT, Watanabe M, Engevik AC, Goldstein AE, Hodges CA, Goldenring JR. Lysophosphatidic Acid Increases Maturation of Brush Borders and SGLT1 Activity in MYO5B-deficient Mice, a Model of Microvillus Inclusion Disease. Gastroenterology. 2020 Oct;159(4):1390-1405.e20.
GRI 977143是一种针对溶血磷脂酸受体2（LPA2）的非脂类激动剂，EC50值为3.3μM[1]。它能够模拟天然配体溶血磷脂酸（LPA）的功能，激活LPA2下游的信号通路（如 G 蛋白偶联通路）[2]，从而调控细胞增殖、迁移、存活和炎症反应等过程[3]。
在体外，在LPA2转导的小鼠胚胎成纤维(MEF)细胞中，GRI 977143（10μM）处理细胞24h即可促进其生长[1]。GRI 977143（1μM）处理非小细胞肺癌（NSCLC）细胞30min，可显著提高NSCLC细胞对顺铂(CDDP)的抵抗力，细胞的存活率显著提高[4]。15 Gy γ照射小鼠胚胎成纤维MEF细胞后，用GRI 977143（10μM）处理MEF细胞1h，可抑制Caspase9的表达，从而减轻γ辐射诱导的细胞凋亡[5]。
在体内，在卵清蛋白（OVA）诱导的小鼠哮喘模型中，于OVA致敏前30min以1mg/kg剂量单次腹腔注射GRI 977143，可显著抑制嗜酸性粒细胞和淋巴细胞水平的升高[6]。连续四日每日腹腔注射GRI 977143（3mg/kg）可激活LPA2，从而改善肌球蛋白VB(MYO5B)基因敲除小鼠的分泌性腹泻症状[7]。