LY2157299

LY2157299 is an oral and selective TGF-β receptor type I (TGF-βRI) kinase inhibitor with an IC₅₀ value of 56nM. LY2157299 specifically targets and binds to the kinase domain of TGF-βR1, thereby preventing the activation of TGF-β-mediated signaling pathways^[1]. LY2157299 exhibits anticancer effects and widely applied in the treatment of various cancer types, including ovrian cancer, hepatocellular carcinoma, and neuroblastoma^[2][3][4].

In vitro, LY2157299 (0, 0.1, 0.2, 0.6, 1.0, 1.5mM) treated high-grade serous ovarian cancer cells (HGSOC) for 72h inhibited TGF-β signaling characterized by the downregulation of p-SMAD2 and p-SMAD3 and also inhibited important phenotypic characteristics of HGSOC cells, including proliferation, migration, and invasion^[2]. LY2157299 (0.1, 1.0, 10, and 100µM) incubated hepatocellular carcinoma cells (HCC) for 72- and 96-hour displayed limited TGF-β independent antiproliferative effects only at high concentration (100µM) and strong anti-invasive effects at 10µM^[3]. LY2157299 (5µM) pretreated neuroblastoma with/without TGF-β1 (10ng/ml) for 24h showed that LY2157299 inhibited the suppressive effects of TGFβ1 on NK cells and enhanced the cytotoxicity effect against neuroblastoma cells^[4].

In vivo, LY2157299 administed orally (75mg/kg, twice-daily, 7 days a week) 2 days before xenografting, then continuously for 4 weeks significantly slowed the growth of tumors in ovarian cancer cells (OVCAR8) derived xenografts (OV8-CDX) model^[2]. LY2157299 administered intragastrically (75mg/kg) for 2 days (0 and 24h) alleviated the histopathological alterations of the pancreas in acute pancreatitis models by inhibiting activation of TGF-β1 signals, inducing acinar cell apoptosis and reducing proinflammatory cytokines^[5]. LY2157299 injected intraperitoneally (150mg/kg) three times a week for 2 weeks showed a normal Hepatic Index value, a reduction of balloon-like degeneration, necrosis, inflammatory cells in the portal area and pseudolobules with thick fibrous septa in liver from fibrotic rats^[6].

References:
[1]Cong L, Xia Z K, Yang R Y.Targeting the TGF-β receptor with kinase inhibitors for scleroderma therapy. Arch Pharm (Weinheim). 2014 Sep;347(9):609-15.
[2]Zhang Q, Hou X N, Evans J B, et al. LY2157299 Monohydrate, a TGF-βR1 Inhibitor, Suppresses Tumor Growth and Ascites Development in Ovarian Cancer. Cancers (Basel). 2018 Aug 7;10(8):260.
[3]Serova M, Tijeras-Raballand A, Santos D C, et al. Effects of TGF-beta signalling inhibition with galunisertib (LY2157299) in hepatocellular carcinoma models and in ex vivo whole tumor tissue samples from patients. Oncotarget. 2015 Aug 28;6(25):21614-27.
[4]Tran C H, Wan Z S, Sheard A M, et al.TGFβR1 Blockade with Galunisertib (LY2157299) Enhances Anti-Neuroblastoma Activity of the Anti-GD2 Antibody Dinutuximab (ch14.18) with Natural Killer Cells. Clin Cancer Res. 2017 Feb 1;23(3):804-813.
[5] Liu X, Yu M, Chen Y, Zhang J. Galunisertib (LY2157299), a transforming growth factor-β receptor I kinase inhibitor, attenuates acute pancreatitis in rats. Braz J Med Biol Res. 2016 Aug 8;49(9):e5388.
[6]Panzarini E, Leporatti S, Tenuzzo A B, et al. Therapeutic Effect of Polymeric Nanomicelles Formulation of LY2157299-Galunisertib on CCl4-Induced Liver Fibrosis in Rats. J Pers Med. 2022 Nov 1;12(11):1812.

LY2157299是一种口服的、选择性TGF-β受体I型（TGF-βRI）激酶抑制剂，IC₅₀值为56nM。LY2157299特异性靶向并结合TGF-βR1的激酶结构域，从而阻止TGF-β介导的信号通路的激活^[1]。LY2157299具有抗癌作用，广泛应用于多种癌症的治疗，包括卵巢癌、肝癌、神经母细胞瘤^[2][3][4]。

在体外实验中，LY2157299（0、0.1、0.2、0.6、1.0、1.5mM）对卵巢癌（High-Grade Serous Ovarian Cancer HGSOC）细胞作用72h可以下调p-SMAD2和p-SMAD3、抑制TGF-β信号，并抑制HGSOC细胞的增殖、迁移和侵袭等重要表型特征^[2]。LY2157299（0.1、1.0、10和100µM）培养肝癌细胞（Hepatocellular Carcinoma Cells HCC）72和96小时，仅在高浓度（100µM）下显示有限的、TGF-β独立的抗细胞增殖作用，在10µM下显示较强的抗侵袭作用^[3]。LY2157299（5µM）协同或不协同TGF-β1（10ng/ml）预处理神经母细胞瘤24h后，LY2157299抑制了TGF-β1对NK细胞的抑制作用并增强NK对神经母细胞瘤细胞的细胞毒性作用^[4]。

在体内，LY2157299口服给药（75mg/kg，每日两次，每周7天），在异种移植前2天开始，然后连续给药4周，显著减缓了卵巢癌细胞（OVCAR8）衍生的异种移植模型（OV8-CDX）中肿瘤的生长^[2]。LY2157299通过胃管给药（75mg/kg），给药2天（0和24h），通过抑制TGF-β1信号的激活，诱导腺泡细胞凋亡，产生促炎细胞因子，减轻了急性胰腺炎模型中胰腺的组织病理学改变^[5]。LY2157299腹腔注射（150mg/kg）肝纤维化大鼠模型，每周3次，持续2周，结果显示肝脏指数值正常，肝细胞气球样变、坏死、门静脉周围炎症细胞和厚纤维间隔的假小叶减少^[6]。