GW3965 HCl is a selective, orally active, nonsteroidal agonist for liver X receptors (LXR)[1]. In a cell-free ligand sensing assay, GW3965 HCl recruited steroid receptor coactivator 1 (SRC1) to human LXRα with an EC50 of 125nM. In a cell-based reporter gene assay, GW3965 HCl acted as a full agonist for hLXRα and hLXRβ with EC50 of 190nM and 30nM, respectively[2]. GW3965 HCl was able to affect glucose and lipid metabolism as well as inflammatory responses[3].
In vitro, treatment of BxPC-3 and PANC-1 cells with GW3965 HCl (10µM) for 48h resulted in significant upregulation of 83 metabolites and downregulation of 367 metabolites in BxPC-3 cells, and upregulation of 216 metabolites and downregulation of 81 metabolites in PANC-1 cells[4]. Treatment of human hepatocytes with GW3965 HCl (2μM) for 48h increased the ratio of monounsaturated fatty acids to saturated fatty acids, promoted phosphatidylethanolamine and phosphatidylcholine remodeling, induced the expression of LXR target genes SREBPC1 and ABCA1, and reduced PEPCK expression[5].
In vivo, oral treatment of U87/EGFRvIII cell xenograft mice with GW3965 HCl (40mg/kg/day) for 12 days significantly inhibited tumor growth, induced ABCA1 expression, and reduced LDLR expression[6]. Oral treatment of APP/PS1 mice with GW3965 HCl (33mg/kg/day) for 8 weeks significantly increased apolipoprotein E (apoE) levels in brain tissue and cerebrospinal fluid, and significantly reduced hippocampal and whole brain amyloid burden[7].
References:
[1] Peng D, Hiipakka R A, Xie J T, et al. A novel potent synthetic steroidal liver X receptor agonist lowers plasma cholesterol and triglycerides and reduces atherosclerosis in LDLR–/–mice[J]. British journal of pharmacology, 2011, 162(8): 1792-1804.
[2] Collins J L, Fivush A M, Watson M A, et al. Identification of a nonsteroidal liver X receptor agonist through parallel array synthesis of tertiary amines[J]. Journal of medicinal chemistry, 2002, 45(10): 1963-1966.
[3] Baranowski M. Biological role of liver X receptors[J]. J Physiol Pharmacol, 2008, 59(Suppl 7): 31-55.
[4] Srivastava S, Widmann S, Ho C, et al. Novel liver X receptor ligand GAC0001E5 disrupts glutamine metabolism and induces oxidative stress in pancreatic cancer cells[J]. International Journal of Molecular Sciences, 2020, 21(24): 9622.
[5] Santinha D, Klopot A, Marques I, et al. Lipidomic analysis of human primary hepatocytes following LXR activation with GW3965 identifies AGXT2L1 as a main target associated to changes in phosphatidylethanolamine[J]. The Journal of Steroid Biochemistry and Molecular Biology, 2020, 198: 105558.
[6] Guo D, Reinitz F, Youssef M, et al. An LXR agonist promotes glioblastoma cell death through inhibition of an EGFR/AKT/SREBP-1/LDLR–dependent pathway[J]. Cancer discovery, 2011, 1(5): 442-456.
[7] Donkin J J, Stukas S, Hirsch-Reinshagen V, et al. ATP-binding cassette transporter A1 mediates the beneficial effects of the liver X receptor agonist GW3965 on object recognition memory and amyloid burden in amyloid precursor protein/presenilin 1 mice[J]. Journal of Biological Chemistry, 2010, 285(44): 34144-34154.
GW3965 HCl是一种选择性的口服活性非甾体激动剂，用于肝X受体（LXR）[1]。在无细胞配体传感试验中，GW3965 HCl将类固醇受体共激活因子1（SRC1）募集至人LXRα，EC50为125nM。在基于细胞的报告基因测定中，GW3965 HCl作为hLXRα和hLXRβ的完全激动剂，EC50分别为190nM和30nM[2]。GW3965 HCl能够影响葡萄糖和脂质代谢以及炎症反应[3]。
在体外，GW3965 HCl（10µM）处理BxPC-3和PANC-1细胞48h，导致了BxPC-3细胞内83种代谢物显著上调和367种代谢物下调，导致了PANC-1细胞内216 种代谢物上调和81种代谢物下调[4]。GW3965 HCl（2μM）处理人肝细胞48h，增加了单不饱和脂肪酸/饱和脂肪酸的比例，促进了磷脂酰乙醇胺和磷脂酰胆碱重塑，诱导了LXR靶基因SREBPC1和ABCA1表达，减少了PEPCK表达[5]。
在体内，GW3965 HCl（40mg/kg/day）通过口服治疗U87/EGFRvIII细胞异种移植小鼠12天，显著抑制了肿瘤生长，诱导了ABCA1表达，降低了LDLR表达[6]。GW3965 HCl（33mg/kg/day）通过口服治疗APP/PS1小鼠8周，显著升高了脑组织和脑脊液中载脂蛋白E（apoE）水平，显著降低了海马和全脑淀粉样蛋白负荷[7]。