Edg-2 receptor inhibitor 1

SAR-100842 is a lysophaphatidic acid 1 (LPA1/Edg-2) receptor inhibitor.

Signaling Pathways >> GPCR/G Protein >> LPL Receptor

Research Areas >> Inflammation/Immunology

LPA1/Edg-2 Receptor[1][2]

SAR-100842 (Compound Example 14) is an Edg-2 receptor inhibitor extracted from patent WO2009135590A1, has an IC50 of <0.1 μM[1]. SAR-100842 (SAR100842) is a lysophaphatidic acid receptor 1 (LPA1) inhibitor, which can be used for the treatment of systemic sclerosis and related fibrotic diseases[2]. In LPAR1-based in vitro inhibition of LPA-stimulated Ca2+ flux in a cell based assay, SAR-100842 (SAR100842) has an IC50 of 65 nM; and shows no activity up to 10 μM on LPA2, LPA3 or LPA5 in similar calcium assays. Increasing doses of SAR-100842 do not significantly affect proliferation of either cell line over time. There is a significant decrease in the ability of cells to migrate in a wound healing assay in a dose dependent manner, 64% reduction (p<0.0001) with 5 μM SAR-100842 after 72 hours in MDA-MB-231T and 67% reduction (p<0.0001) with 50 μM SAR-100842 after 48 hours in 4T1-Luc2. In a Boyden chamber assay for motility, 50 μM SAR100842 reduces the migration of MDA-MD-231T cells through a collagen membrane by 1.92-fold (p=0.0004) and 3.15-fold (p<0.0001) to FBS and LPA chemoattractants, respectively. In 4T1-Luc2 cells 50 μM SAR-100842 reduces migration by 10.8-fold (p=0.01) and 13.6-fold (p=0.007) to FBS and LPA, respectively[3].

SAR-100842 (SAR100842) has a half-life of 4.9 h and a Cmax of 5600 ng/mL after a 30 mg/kg oral dosing in mice[3].

Mice[3] To study SAR-100842 in the ovarian cancer lines, 6-8 week old athymic nu/nu mice receive either 1.0×106 SKVO3 cells or 3.5×106 OVCAR5 cells (n=33 mice per line) in an intraperitoneal injection. On day two post cell injection, mice are randomized to three groups. Group one begin vehicle on day 2, group two begin 30 mg/kg SAR-100842 twice daily on day two for the duration of the experiment, and group three begin 30 mg/kg SAR-100842 twice daily on day 10 for the duration of the experiment. On day 70 post cell injection all mice are euthanized and necropsied. Liver, abdominal lymph nodes or masses, omentum, peritoneum and any other organ suspected of harboring tumor are collected, fixed in 10% NBF and prepared for histological analysis[3].

[1]. SCHAEFER, Matthias, et al. ACYLAMINO-SUBSTITUTED FUSED CYCLOPENTANECARBOXYLIC ACID DERIVATIVES AND THEIR USE AS PHARMACEUTICALS. WO2009135590A1.

[2]. Kihara Y, et al. Lysophospholipid receptors in drug discovery. Exp Cell Res. 2015 May 1;333(2):171-7.

[3]. Brooks D, et al. Limited fibrosis accompanies triple-negative breast cancer metastasis in multiple model systems and is not a preventive target. Oncotarget. 2018 May 4;9(34):23462-23481.

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