LY2109761

LY2109761（CAS号700874-71-1）是一种选择性的I/II型TGF-β受体（TβRI/II）小分子抑制剂，Ki值分别为38 nM和300 nM[1]。在TβRI 酶实验中，IC50值为69 nM。晶体结构显示LY2109761与TGF-βR1激酶结构域的ATP结合位点相结合。LY2109761对其它的激酶（包括Lck、Sapk2α、MKK6、Fyn和JNK3）具有较弱的抑制活性（20 μM时18-89%的抑制）[2]。

在临床前研究中，LY2109761具有潜在的抗肿瘤活性。TGF-β信号通路的调控缺失与各种恶性肿瘤的发生相关。在胰腺癌细胞中，LY2109761抑制细胞增殖、迁移和侵袭，诱导细胞凋亡。在转移性胰腺癌小鼠模型中，LY2109761与gemcitabine联合给药抑制肿瘤生长和转移[1]。在骨髓 - 单核细胞白血病细胞中，LY2109761抑制TGF-beta1的抗凋亡效应[3]。在胶质母细胞瘤（GBM）细胞系和原位颅内移植模型中，LY2109761增加放射敏感性，导致存活期的延长[4]。此外，在小鼠模型中，LY2109761减少放射诱导的肺炎和肺纤维化[5]。

参考文献：
[1]Melisi D, Ishiyama S, Sclabas GM et al.  LY2109761, a novel transforming growth factor beta receptor type I and type II dual inhibitor, as a therapeutic approach to suppressing pancreatic cancer metastasis. Mol Cancer Ther 2008; 7: 829-840.
[2]Li HY, McMillen WT, Heap CR et al.  Optimization of a dihydropyrrolopyrazole series of transforming growth factor-beta type I receptor kinase domain inhibitors: discovery of an orally bioavailable transforming growth factor-beta receptor type I inhibitor as antitumor agent. J Med Chem 2008; 51: 2302-2306.
[3]Xu Y, Tabe Y, Jin L et al.  TGF-beta receptor kinase inhibitor LY2109761 reverses the anti-apoptotic effects of TGF-beta1 in myelo-monocytic leukaemic cells co-cultured with stromal cells. Br J Haematol 2008; 142: 192-201.
[4]Zhang M, Kleber S, Rohrich M et al.  Blockade of TGF-beta signaling by the TGFbetaR-I kinase inhibitor LY2109761 enhances radiation response and prolongs survival in glioblastoma. Cancer Res 2011; 71: 7155-7167.
[5]Flechsig P, Dadrich M, Bickelhaupt S et al.  LY2109761 attenuates radiation-induced pulmonary murine fibrosis via reversal of TGF-beta and BMP-associated proinflammatory and proangiogenic signals. Clin Cancer Res 2012; 18: 3616-3627.