GW 6471 is a potent dual PARα/γ antagonist with anti-proliferative activity in vivo and in vitro. The IC50 values of GW 6471 binding affinity to PPARα and PPARγ are 95.3 ± 42.0 nM and 39.4 ± 18.2 nM, respectively[1]. GW 6471 can be used in cancer research[1-3].
GW 6471 inhibits the growth (0.5 μM to 8 μM), migration and invasion (0.5 μM to 10 μM) of human mesothelioma cells and, at higher concentrations, reduces the viability of human mesothelioma cell line VGE62 and murine mesothelioma cell lines AB1 and AE17[1]. GW 6471 reduces HNPGL cell viability and growth by inducing cell cycle arrest and caspase-dependent apoptosis with IC50 values of 10 μM and 16 μM in PTJ64i and PTJ86i cells, respectively. The effect of GW 6471 on HNPGL cells is associated with inhibition of the PI3K/GSK3β/β-catenin signaling pathway[2].
GW 6471 (20 mg/kg) inhibited tumor growth in Caki-1 cell xenograft mouse models and the expression of c-Myc in mouse tumor tissues. No toxicity was observed at a dose of 20 mg/kg, and renal and liver functions were not adversely affected[3]. Medial prefrontal cortex injection of GW6471 (10 μg) in rats delayed the onset of the early second phase of formalin-induced nociceptive behavior[4].
References:
[1] Morales M L O, Rinaldi C A, de Jong E, et al. PPARα and PPARγ activation is associated with pleural mesothelioma invasion but therapeutic inhibition is ineffective[J]. Iscience, 2022, 25(1).
[2] Florio R, De Lellis L, di Giacomo V, et al. Effects of PPARα inhibition in head and neck paraganglioma cells[J]. PLoS One, 2017, 12(6): e0178995.
[3] Abu Aboud O, Donohoe D, Bultman S, Fitch M, Riiff T, Hellerstein M, Weiss RH. PPARα inhibition modulates multiple reprogrammed metabolic pathways in kidney cancer and attenuates tumor growth. Am J Physiol Cell Physiol. 2015 Jun 1;308(11):C890-8.
[4] Okine B N, Rea K, Olango W M, et al. A role for PPAR α in the medial prefrontal cortex in formalin‐evoked nociceptive responding in rats[J]. British journal of pharmacology, 2014, 171(6): 1462-1471.
GW 6471 是一种有效的双重 PPARα/γ 拮抗剂，其具有体内外抗增殖活性。GW 6471与 PPARα 和 PPARγ 的结合亲和力的IC50 值分别为95.3 ± 42.0 nM 和39.4 ± 18.2 nM[1]。GW 6471可用于癌症的研究[1-3]。
GW 6471 可以抑制人间皮瘤细胞的生长（0.5 μM 至 8 μM）、迁移和侵袭（0.5 μM 至 10 μM），在较高浓度下还降低了人间皮瘤细胞系VGE62以及鼠间皮瘤细胞系 AB1 和 AE17 的活力[1]。GW 6471 通过诱导细胞周期停滞和 caspase 依赖性细胞凋亡来降低 HNPGL 细胞活力和生长，在PTJ64i 与PTJ86i 细胞中的 IC50 分为 10 μM和16 μM，并且GW 6471 对 HNPGL 细胞的作用与抑制 PI3K/GSK3β/β-catenin 信号通路有关[2]。
GW 6471（20 mg/kg）可抑制Caki-1细胞异种移植小鼠模型中肿瘤的生长及小鼠肿瘤组织中c-Myc 的表达，剂量为20 mg/kg时未观察到毒性，肾功能和肝功能未受到不利影响[3]。在大鼠内侧前额叶皮质（mPFC）内注射GW6471（10 μg）可使福尔马林诱发的伤害性行为的早期第二阶段延迟发作[4]。