LGK-974 is a potent and specific inhibitor of Porcupine (PORCN)[1]. By inhibiting PORCN, LGK-974 effectively inhibits endogenous Wnt/β‑catenin signaling, which is critical in various biological processes, including cell proliferation, differentiation, and migration[2]. LGK-974 is commonly utilized in cancer research, particularly in the study of its potential to inhibit tumor growth[3] and modulate the tumor microenvironment[4].
LGK-974 can reduce Wnt-dependent AXIN2 mRNA levels in HN30 cells with an IC50 of 0.3nM[5]. In HepG2 cells, treatment with LGK-974 at 10µM for 6h can increase radiosensitivity by elevating reactive oxygen species (ROS) levels[6].
LGK-974 (3mg/kg, 7d, oral) treatment can attenuate the monocytic response and improves the healing process following myocardial infarction in Mice with induced ischemia/reperfusion (I/R) injury[7]. Repeated systemic injections of LGK-974 (2mg/kg, twice daily for 8d, i.p.) can prevent the development of chemotherapy-induced neuropathic pain CINP in rats[8].
References:
[1]. Morgan JT, Raghunathan VK, Chang YR, et al. Wnt inhibition induces persistent increases in intrinsic stiffness of human trabecular meshwork cells. Exp Eye Res. 2015 Mar;132:174-8. doi: 10.1016/j.exer.2015.01.025. Epub 2015 Jan 30. PMID: 25639201; PMCID: PMC4352377.
[2]. Zhang Y, Wang X. Targeting the Wnt/β-catenin signaling pathway in cancer. J Hematol Oncol. 2020 Dec 4;13(1):165. doi: 10.1186/s13045-020-00990-3. PMID: 33276800; PMCID: PMC7716495.
[3]. Guimaraes PPG, Tan M, Tammela T, et al. Potent in vivo lung cancer Wnt signaling inhibition via cyclodextrin-LGK974 inclusion complexes. J Control Release. 2018 Nov 28;290:75-87. doi: 10.1016/j.jconrel.2018.09.025. Epub 2018 Oct 2. PMID: 30290244; PMCID: PMC6441337.
[4]. Tang Y, Jiang M, Chen A, et al. Porcupine inhibitor LGK‑974 inhibits Wnt/β‑catenin signaling and modifies tumor‑associated macrophages resulting in inhibition of the malignant behaviors of non‑small cell lung cancer cells. Mol Med Rep. 2021 Aug;24(2):550. doi: 10.3892/mmr.2021.12189. Epub 2021 Jun 3. PMID: 34080032; PMCID: PMC8185506.
[5]. Liu J, Pan S, Hsieh MH, et al. Targeting Wnt-driven cancer through the inhibition of Porcupine by LGK974. Proc Natl Acad Sci U S A. 2013 Dec 10;110(50):20224-9. doi: 10.1073/pnas.1314239110. Epub 2013 Nov 25. PMID: 24277854; PMCID: PMC3864356.
[6]. Tian D, Shi Y, Chen D, et al. The Wnt inhibitor LGK-974 enhances radiosensitivity of HepG2 cells by modulating Nrf2 signaling. Int J Oncol. 2017 Aug;51(2):545-554. doi: 10.3892/ijo.2017.4042. Epub 2017 Jun 14. PMID: 28627706.
[7]. Meyer IS, Li X, Meyer C, et al. Blockade of Wnt Secretion Attenuates Myocardial Ischemia-Reperfusion Injury by Modulating the Inflammatory Response. Int J Mol Sci. 2022 Oct 14;23(20):12252. doi: 10.3390/ijms232012252. PMID: 36293109; PMCID: PMC9602582.
[8]. Kim HK, Bae J, Lee SH, et al. Blockers of Wnt3a, Wnt10a, or β-Catenin Prevent Chemotherapy-Induced Neuropathic Pain In Vivo. Neurotherapeutics. 2021 Jan;18(1):601-614. doi: 10.1007/s13311-020-00956-w. Epub 2020 Oct 30. PMID: 33128175; PMCID: PMC8116404.
LGK-974是一种高效且特异的Porcupine（PORCN）抑制剂[1]。通过抑制PORCN，LGK-974可以有效抑制内源性Wnt/β-连环蛋白信号通路，该信号通路在细胞增殖、分化和迁移等多种生物过程中起关键作用[2]。LGK-974常用于癌症研究，特别是在抑制肿瘤生长[3]和调节肿瘤微环境的潜力研究中[4]。
LGK-974可在HN30细胞中以0.3nM的IC50降低Wnt依赖的AXIN2 mRNA水平[5]。在HepG2细胞中，使用10µM的LGK974处理6小时可通过增加活性氧（ROS）水平提高放射敏感性[6]。
LGK-974（3mg/kg，7天，口服）治疗可减轻单核细胞反应，并改善小鼠在诱导缺血/再灌注（I/R）损伤后的心肌梗死愈合过程[7]。反复系统注射LGK-974（2mg/kg，每天两次，共8天，腹腔注射）可预防大鼠化疗诱导的神经病理性疼痛（CINP）[8]。