G007-LK is a potent and selective inhibitor of TNKS1 (IC50=46nM) and TNKS2 (IC50=25nM)[1-2]. G007-LK reduces Wnt/β-catenin signaling by inhibiting tankyrase, which prevents AXIN degradation and promotes β-catenin destabilization. G007-LK is used in research related to colorectal cancer, hepatocellular carcinoma, and small cell lung cancer[3-4].
In vitro, G007-LK (50-1000nM) was used to treat patient-derived glioma stem cells (GSCs) for 14 days. G007-LK significantly inhibited the proliferation and sphere formation of GSCs, reduced the expression of downstream target genes of the WNT/β-catenin and YAP/TAZ signaling pathways, and stabilized AXIN1, AMOT, and AMOTL2 proteins[5]. G007-LK (2.5-20μM) was also used to treat human hepatocellular carcinoma (HCC) cell lines for 10-14 days. G007-LK significantly inhibited the colony-forming ability of HCC cells, downregulated YAP protein levels and its downstream target gene expression, and upregulated AMOTL1 and AMOTL2 proteins[6].
In vivo, G007-LK (14mg/kg/day) was administered via diet to db/db diabetic mice, starting at 6 weeks of age for 15 weeks. G007-LK significantly reduced body weight, abdominal fat content, hepatic steatosis, and serum cholesterol levels, while increasing white adipose tissue browning, serum adiponectin levels, mitochondrial mass, and fatty acid oxidative metabolism in skeletal muscle[7]. G007-LK (0.015% wt/wt mixed into diet) was also fed to high-fat diet-fed wild-type male mice for 6 months. G007-LK significantly improved glucose tolerance, enhanced insulin sensitivity, and rapidly increased plasma adiponectin levels[8].
References:
[1] Voronkov A, Holsworth DD, Waaler J, et al. Structural basis and SAR for G007-LK, a lead stage 1,2,4-triazole based specific tankyrase 1/2 inhibitor. J Med Chem. 2013 Apr 11;56(7):3012-23.
[2] Norum JH, Skarpen E, Brech A, et al. The tankyrase inhibitor G007-LK inhibits small intestine LGR5+ stem cell proliferation without altering tissue morphology. Biol Res. 2018 Jan 9;51(1):3.
[3] Jia J, Qiao Y, Pilo MG, et al. Tankyrase inhibitors suppress hepatocellular carcinoma cell growth via modulating the Hippo cascade. PLoS One. 2017 Sep 6;12(9):e0184068.
[4] Thorvaldsen TE, Pedersen NM, Wenzel EM, et al. Structure, Dynamics, and Functionality of Tankyrase Inhibitor-Induced Degradasomes. Mol Cancer Res. 2015 Nov;13(11):1487-501.
[5] Kierulf-Vieira KS, Sandberg CJ, Waaler J, et al. A Small-Molecule Tankyrase Inhibitor Reduces Glioma Stem Cell Proliferation and Sphere Formation. Cancers (Basel). 2020 Jun 19;12(6):1630.
[6] Jia J, Qiao Y, Pilo MG, et al. Tankyrase inhibitors suppress hepatocellular carcinoma cell growth via modulating the Hippo cascade. PLoS One. 2017 Sep 6;12(9):e0184068.
[7] Wang H, Kuusela S, Rinnankoski-Tuikka R, et al. Tankyrase inhibition ameliorates lipid disorder via suppression of PGC-1α PARylation in db/db mice. Int J Obes (Lond). 2020 Aug;44(8):1691-1702.
[8] Zhong L, Ding Y, Bandyopadhyay G, et al. The PARsylation activity of tankyrase in adipose tissue modulates systemic glucose metabolism in mice. Diabetologia. 2016 Mar;59(3):582-91.
G007-LK是一种有效的、选择性的TNKS1（IC50=46nM）和TNKS2（IC50=25nM）抑制剂[1-2]。G007-LK可通过抑制tankyrase来减少Wnt/β-catenin信号传导，防止AXIN降解，促进β-catenin去稳定化。G007-LK可用于结直肠癌、肝细胞癌、小细胞肺癌等相关研究[3-4]。
在体外，G007-LK（50-1000nM）处理人源胶质瘤干细胞（GSCs）14天，G007-LK显著抑制GSCs的增殖和肿瘤球形成，并降低WNT/β-catenin和YAP/TAZ信号通路下游靶基因（如AXIN2、CTGF）的表达，同时稳定AXIN1、AMOT和AMOTL2蛋白[5]。G007-LK（2.5-20μM）处理人源肝细胞癌（HCC）细胞系10-14天，G007-LK显著抑制HCC细胞的集落形成能力，并下调YAP蛋白水平及其下游靶基因（如CTGF、CYR61）的表达，同时上调AMOTL1和AMOTL2蛋白[6]。
在体内，G007-LK（14mg/kg/day）饲喂处理db/db糖尿病小鼠（从6周龄开始，持续15周），G007-LK显著降低小鼠体重、腹部脂肪含量、肝脏脂肪变性和血清胆固醇水平，并增加白色脂肪组织（WAT）褐变、血清脂联素水平以及骨骼肌的线粒体质量和脂肪酸氧化代谢[7]。G007-LK（混入饲料， 0.015%wt/wt）饲喂处理高脂饮食（HFD）喂养的野生型雄性小鼠（持续6个月），G007-LK显著改善葡萄糖耐量、增强胰岛素敏感性，并迅速提高血浆脂联素水平[8]。