LY364947 is a potent ATP-competitive inhibitor of TGFβR-I with IC50 of 59nM[1]. TGFβRI is a serine/threonine kinase type I receptor of the TGF-β pathway that, upon activation, phosphorylates Smad2/3 to mediate fibrosis, immune suppression, and tumor progression[2]. LY364947 is widely used in research of TGF-β-related fibrosis, cancer, and immune-modulation by blocking the TGF-β/Smad signaling cascade[3][4].
In vitro, treatment of human dermal lymphatic microvascular endothelial cells (HDLECs) with LY364947 (3μM; 24h) significantly induces the expression of Prox1 and LYVE-1 and inhibits TGF-β1-induced Smad2 phosphorylation, while promoting cord formation and cell migration[5]. Treatment of CML leukemia-initiating cells (LICs) with LY364947 (10µM; 2h) increased the nuclear export of Foxo3a, decreased the phosphorylation level of Smad2/3, and impaired cell colony forming ability[6].
In vivo, LY364947 (5mg/kg; i.p.; 4 days) enhanced liver regeneration, increased cell proliferation (measured by PCNA, phosphorylated histone 3, p21) levels, recovered of CCl4-metabolizing enzyme CYP2E1 expression in hepatocytes, and improved liver function in a mouse model of acute liver injury induced by carbon tetrachloride (CCL4)[3]. LY364947 (50nM; intravitreal injection; 7 days) almost completely prevented capillary degeneration and retinal vascular damage and slightly attenuated the reduction in number of cells in the ganglion cell layer in a rat model of retinal degeneration induced by N-methyl-D-Aspartate (NMDA)[7].
References:
[1] Peng SB, Yan L, Xia X, et al. Kinetic characterization of novel pyrazole TGF-beta receptor I kinase inhibitors and their blockade of the epithelial-mesenchymal transition. Biochemistry. 2005;44(7):2293-2304.
[2] Hu X, Zuckerman KS. Transforming growth factor: signal transduction pathways, cell cycle mediation, and effects on hematopoiesis. J Hematother Stem Cell Res. 2001;10(1):67-74.
[3] Tschernia NP, Gulley JL. Tumor in the Crossfire: Inhibiting TGF-β to Enhance Cancer Immunotherapy. BioDrugs. 2022;36(2):153-180.
[4] Karkampouna S, Goumans MJ, Ten Dijke P, Dooley S, Kruithof-de Julio M. Inhibition of TGFβ type I receptor activity facilitates liver regeneration upon acute CCl4 intoxication in mice. Arch Toxicol. 2016;90(2):347-357.
[5] Oka M, Iwata C, Suzuki HI, et al. Inhibition of endogenous TGF-beta signaling enhances lymphangiogenesis. Blood. 2008;111(9):4571-4579.
[6] Naka K, Hoshii T, Muraguchi T, et al. TGF-beta-FOXO signalling maintains leukaemia-initiating cells in chronic myeloid leukaemia. Nature. 2010;463(7281):676-680.
[7] Ueda K, Nakahara T, Mori A, Sakamoto K, Ishii K. Protective effects of TGF-β inhibitors in a rat model of NMDA-induced retinal degeneration. Eur J Pharmacol. 2013;699(1-3):188-193.
LY364947是一种强效的ATP竞争性TGFβR-I抑制剂，其IC50为59nM[1]。TGFβRI是TGF-β通路的I型受体丝氨酸/苏氨酸激酶，激活后磷酸化Smad2/3以介导纤维化、免疫抑制和肿瘤进展[2]。LY364947通过阻断TGF-β/Smad信号通路被广泛用于研究TGF-β相关的纤维化、癌症和免疫调节[3][4]。
在体外，用LY364947（3μM；24小时）处理人皮肤淋巴管微血管内皮细胞（HDLECs）显著诱导Prox1和LYVE-1的表达，并抑制TGF-β1诱导的Smad2磷酸化，同时促进管状结构形成和细胞迁移[5]。用LY364947（10µM；2小时）处理CML白血病起始细胞（LICs）增加了Foxo3a的核外移，降低了Smad2/3的磷酸化水平，并损害了细胞集落形成能力[6]。
在体内，LY364947（5mg/kg；腹腔注射；4天）增强了四氯化碳（CCL4）诱导的急性肝损伤小鼠模型中的肝再生，增加了细胞增殖（通过PCNA、磷酸化组蛋白3、p21测量）水平，恢复了肝细胞中CCL4代谢酶CYP2E1的表达，并改善了肝功能[3]。LY364947（50nM；玻璃体腔注射；7天）几乎完全阻止了N-甲基-D-天冬氨酸（NMDA）诱导的大鼠视网膜退化模型中毛细血管退化和视网膜血管损伤，并轻微减轻了视网膜神经节细胞层细胞数量的减少[7]。