LY2109761是一種小分子抑制劑，選擇性靶向I型和II型TGF-β受體((TβRI/II))，Ki分別為38 nM和300nM[1]。它在TβRI酶法測定中給出69 nM的IC50值[2]。晶體結(jié)構(gòu)顯示LY2109761與TGF-β R1激酶結(jié)構(gòu)域的ATP結(jié)合位點(diǎn)結(jié)合[2]。據(jù)報(bào)道，其他激酶的抑制活性較弱，包括Lck、Sapk2α、MKK6、Fyn和JNK 3(20M時(shí)抑制率為18–89%)[2]。

   LY2109761在臨床前研究中顯示出潛在的抗腫瘤活性。TGF-β信號通路的異常與多種惡性腫瘤相關(guān)。LY2109761抑制胰腺癌細(xì)胞的增殖、遷移和侵襲，并誘導(dǎo)其凋亡[1]。當(dāng)與吉西他濱聯(lián)合使用時(shí)，它可以抑制轉(zhuǎn)移性胰腺癌小鼠模型中的腫瘤生長和轉(zhuǎn)移[1]。它還抑制了TGF-β1在骨髓-單核細(xì)胞白血病細(xì)胞中的抗凋亡作用[3]。GBM細(xì)胞系和原位顱內(nèi)模型的結(jié)果表明，LY2109761增加了放射敏感性，并延長了膠質(zhì)母細(xì)胞瘤的生存期[4]。此外，LY2109761減少了小鼠模型中輻射誘導(dǎo)的肺炎和肺纖維化[5]。

產(chǎn)品性質(zhì)：

Cas No.：700874-71-1

化學(xué)名： 4-[2-[4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)quinolin-7-yl]oxyethyl]morpholine

Canonical SMILES：C1CC2=C(C(=NN2C1)C3=CC=CC=N3)C4=C5C=CC(=CC5=NC=C4)OCCN6CCOCC6

分子式：C26H27N5O2

分子量：441.52

溶解度：≥ 22.1mg/mL in DMSO

儲存條件：Store at -20°C

注意事項(xiàng)：

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References:

[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] [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.