TSI-01 is a selective inhibitor of lysophosphatidylcholine acyltransferase 2 (LPCAT2) with IC50 values of 0.47 and 3.02 µM for human LPCAT2 and LPCAT1, respectively. LPLAT selectively incorporates fatty chains into lysophospholipids to affect the fatty acid composition of membrane glycerophospholipids [1, 2]. TSI-01 can inhibit the production of platelet-activating factor (PAF) in macrophages, which is rapidly biosynthesized by lyso-PAF acetyltransferase (lyso-PAFAT) [3].
In vitro, treatment of HT29 cells with TSI-01 (10 μM) for 48 h significantly prevented lipid droplet accumulation caused by 5-fluorouracil (5-Fu) and oxaliplatin (Oxa) alone or in combination [4]. TSI-01 (0-30 μM) treated endometrial cancer cell lines, inhibited cell proliferation in a dose-dependent manner, with IC50 values of 7.56 μM and 9.31 μM in Ishikawa cell lines and HEC-1A cell lines, respectively, and promoted cell apoptosis[5].
References:
[1] Tarui M, Shindou H, Kumagai K, et al. Selective inhibitors of a PAF biosynthetic enzyme lysophosphatidylcholine acyltransferase 2 [S][J]. Journal of lipid research, 2014, 55(7): 1386-1396.
[2] Valentine W J, Hashidate–Yoshida T, Yamamoto S, et al. Biosynthetic enzymes of membrane glycerophospholipid diversity as therapeutic targets for drug development[J]. Druggable Lipid Signaling Pathways, 2020: 5-27.
[3] Shindou H, Shiraishi S, Tokuoka S M, et al. Relief from neuropathic pain by blocking of the platelet-activating factor–pain loop[J]. The FASEB Journal, 2017, 31(7): 2973.
[4] Cotte A K, Aires V, Fredon M, et al. Lysophosphatidylcholine acyltransferase 2-mediated lipid droplet production supports colorectal cancer chemoresistance[J]. Nature communications, 2018, 9(1): 322.
[5] Zhao T, Sun R, Ma X, et al. Overexpression of LPCAT1 enhances endometrial cancer stemness and metastasis by changing lipid components and activating TGF-β/Smad2/3 signaling pathway: Tumor-promoting effect of LPCAT1 in endometrial cancer[J]. Acta Biochimica Et Biophysica Sinica, 2022, 54(7): 904.
TSI-01是溶血磷脂酰胆碱酰基转移酶2（LPCAT2）的选择性抑制剂，对人 LPCAT2和LPCAT1的IC50值分别为0.47和3.02µM。LPLAT选择性地将脂肪链掺入溶血磷脂中，以影响膜甘油磷脂的脂肪酸组成[1, 2]。TSI-01可以抑制巨噬细胞中血小板激活因子（PAF）的产生，PAF由溶血PAF乙酰转移酶 （lyso-PAFAT）快速生物合成[3]。
在体外，TSI-01（10μM）处理HT29细胞48h，显著防止了由5-氟尿嘧啶（5-Fu）和奥沙利铂（Oxa）单独或联合治疗引起的脂滴积聚[4]。TSI-01（0-30μM）处理子宫内膜癌细胞系，剂量依赖性地抑制了细胞增殖，在Ishikawa细胞系和HEC-1A细胞系中的IC50分别为7.56μM、9.31μM，并促进细胞凋亡[5]。