LY2109761 is an orally available, small-molecule dual TGF-β receptor (TβR) I/II kinase inhibitor (TβRI: Ki = 38nM; TβRII: Ki = 300nM) [1]. By blocking TGF-β signaling and inhibiting Smad2 phosphorylation, LY2109761 downregulates the TGF-β/Smad signaling pathway, exerting anti-proliferative and anti-invasive effects and inducing apoptosis [2-3]. LY2109761 is commonly used to treat cancer [4].
In SKOV3 cells, LY2109761 (0.5-10μM; 72h) treatment inhibited cell growth in a dose- and time-dependent manner [5]. In HepG2 cells, LY2109761 (0.1-100μM; 36h) inhibits cell proliferation by downregulating the phosphorylation of Smad-2 [6]. In AGS cells, LY2109761 (0-40μM; 2h) pretreatment inhibited cell proliferation in a dose-dependent manner after irradiation [7].
In C57BL/6 mice, LY2109761 (50mg/kg; po; twice daily for 4 weeks) attenuates radiation-induced pulmonary fibrosis in mice by reversing TGF-β and BMP-related pro-inflammatory and pro-angiogenic signaling [8]. In L3.6pl/GLT cells xenograft tumor mouse model, LY2109761 (50mg/kg; po; twice daily for 4 weeks) inhibits tumor growth and spontaneous metastasis in orthotopic xenografts in vivo [9].
References:
[1]. Sheen Y Y, Kim M J, Park S A, et al. Targeting the transforming growth factor-β signaling in cancer therapy[J]. Biomolecules & therapeutics, 2013, 21(5): 323.
[2]. Wei G, Xu Q, Liu L, et al. LY2109761 reduces TGF-β1-induced collagen production and contraction in hypertrophic scar fibroblasts[J]. Archives of Dermatological Research, 2018, 310(8): 615-623.
[3]. Chen X, Yan H, Chen Y, et al. Moderate oxidative stress promotes epithelial–mesenchymal transition in the lens epithelial cells via the TGF-β/Smad and Wnt/β-catenin pathways[J]. Molecular and cellular biochemistry, 2021, 476(3): 1631-1642.
[4]. Connolly E C, Saunier E F, Quigley D, et al. Outgrowth of drug-resistant carcinomas expressing markers of tumor aggression after long-term TβRI/II kinase inhibition with LY2109761[J]. Cancer research, 2011, 71(6): 2339-2349.
[5]. Gao Y, Shan N, Zhao C, et al. LY2109761 enhances cisplatin antitumor activity in ovarian cancer cells[J]. International journal of clinical and experimental pathology, 2015, 8(5): 4923.
[6]. He X, Guo X, Zhang H, et al. Mechanism of action and efficacy of LY2109761, a TGF-β receptor inhibitor, targeting tumor microenvironment in liver cancer after TACE[J]. Oncotarget, 2017, 9(1): 1130.
[7]. Yang T, Huang T, Zhang D, et al. TGF-β receptor inhibitor LY2109761 enhances the radiosensitivity of gastric cancer by inactivating the TGF-β/SMAD4 signaling pathway[J]. Aging (Albany NY), 2019, 11(20): 8892.
[8]. Flechsig P, Dadrich M, Bickelhaupt S, et al. LY2109761 attenuates radiation-induced pulmonary murine fibrosis via reversal of TGF-β and BMP-associated proinflammatory and proangiogenic signals[J]. Clinical Cancer Research, 2012, 18(13): 3616-3627.
[9]. Melisi D, Ishiyama S, Sclabas G M, et al. LY2109761, a novel transforming growth factor β receptor type I and type II dual inhibitor, as a therapeutic approach to suppressing pancreatic cancer metastasis[J]. Molecular cancer therapeutics, 2008, 7(4): 829-840.
LY2109761是一种口服小分子双TGF-β受体（TβR）I/II激酶抑制剂（TβRI: Ki = 38nM；TβRII: Ki = 300nM） [1]。LY2109761通过阻断TGF-β信号传导和抑制Smad2磷酸化，下调TGF-β/Smad信号通路，发挥抗增殖、抗侵袭作用，并诱导细胞凋亡 [2-3]。LY2109761常用于治疗癌症 [4]。
在SKOV3细胞中，LY2109761（0.5-10μM；72h）处理以剂量和时间依赖性方式抑制细胞生长 [5]。在HepG2细胞中，LY2109761（0.1-100μM；36h）通过下调Smad-2磷酸化来抑制细胞增殖 [6]。在AGS细胞中，LY2109761（0-40μM；2h）预处理在照射后以剂量依赖性方式抑制细胞增殖 [7]。
在C57BL/6小鼠中，LY2109761（50mg/kg；po；每日两次，持续4周）通过逆转TGF-β和BMP相关的促炎和促血管生成信号，减轻小鼠放射性肺纤维化 [8]。在L3.6pl/GLT细胞异种移植肿瘤小鼠模型中，LY2109761（50mg/kg；po；每日两次，持续4周）可抑制体内原位异种移植瘤的生长和自发转移 [9]。