TC LPA5 4 is a potent LPA5-selective receptor antagonist and a heparanase inhibitor with IC50 values of 0.8μM and 10μM, respectively[1]. TC LPA5 4 can enhance anti-tumor activity and inhibit metastasis by inhibiting LPAR5 and autotaxin in immune cell types[2]. TC LPA5 4 has been widely used in the development of combined therapies to inhibit the progression of multiple myeloma[3].
In vitro, TC LPA5 4 treatment at 1μM for 3 days at a 21% oxygen concentration significantly promoted the growth of DLD-1 cells[4]. The 4-hour treatment with 1μM TC LPA5 4 significantly reduced the maximum respiratory capacity enhancement of LPA-mediated effector CD8 T cells, without affecting the basal respiratory capacity[5]. Treatment of 0.5μM TC LPA5 4 for 16 hours significantly stimulated the motility of HT1080 cells[6].
In vivo, TC LPA5 4 treatment via intraperitoneal injection at a doe of 10mg/kg (5 times a week) for 2 weeks significantly inhibited CGTH‐W3 xenograft growth in mice[7].
References:
[1] Zhang Y, Xiong M, Chen Z, et al. Design principle of heparanase inhibitors: A combined in vitro and in silico study[J]. ACS Medicinal Chemistry Letters, 2024, 15(7): 1032-1040.
[2] Lee S C, Dacheux M A, Norman D D, et al. Regulation of tumor immunity by lysophosphatidic acid[J]. Cancers, 2020, 12(5): 1202.
[3] Zhou X, Yang Y, Hu X, et al. Identification of LPAR1/LPAR5 as novel GPCR partners of GPRC5D for the efficient CAR-T therapy of multiple myeloma[J]. Blood, 2023, 142: 4679.
[4] Yamamoto M, Takai M, Yashiro N, et al. The role of LPA receptor signaling in modulating cellular responses of colon cancer cells co-cultured with lymphoid endothelial cells under hypoxic stress[J]. Tissue and Cell, 2024, 91: 102528.
[5] Turner J A, Fredrickson M A, D’Antonio M, et al. Lysophosphatidic acid modulates CD8 T cell immunosurveillance and metabolism to impair anti-tumor immunity[J]. Nature Communications, 2023, 14(1): 3214.
[6] Takahashi K, Minami K, Otagaki S, et al. Lysophosphatidic acid receptor-2 (LPA2) and LPA5 regulate cellular functions during tumor progression in fibrosarcoma HT1080 cells[J]. Biochemical and biophysical research communications, 2018, 503(4): 2698-2703.
[7] Zhao W J, Zhu L L, Yang W Q, et al. LPAR5 promotes thyroid carcinoma cell proliferation and migration by activating class IA PI3K catalytic subunit p110β[J]. Cancer Science, 2021, 112(4): 1624-1632.
TC LPA5 4是一种强效的LPA5选择性受体拮抗剂和heparanase（乙酰肝素酶）抑制剂，IC50值分别为0.8μM和10μM[1]。TC LPA5 4通过抑制免疫细胞类型中的LPAR5和自分泌运动因子，能够增强抗肿瘤活性并抑制转移[2]。TC LPA5 4已被广泛用于开发抑制多发性骨髓瘤进展的联合疗法[3]。
在体外，在21%氧气浓度下，使用1μM的TC LPA5 4处理DLD-1细胞3天，显著促进了细胞生长[4]。用1μM的TC LPA5 4处理效应CD8 T细胞4小时，显著降低了LPA介导的最大呼吸能力增强，不影响基础呼吸能力[5]。使用0.5μM的TC LPA5 4处理HT1080细胞16小时，显著刺激了细胞运动[6]。
在体内，通过腹腔注射TC LPA5 4，剂量为10mg/kg（每周5次），持续2周，显著抑制了小鼠体内CGTH‐W3异种移植瘤的生长[7]。