受體酪氨酸激酶c-Met在絕大部分的癌及部分肉瘤中高表達(dá)并異常激活，在腫瘤發(fā)生發(fā)展,、侵襲轉(zhuǎn)移,、化療抗性等各個(gè)環(huán)節(jié)均發(fā)揮關(guān)鍵作用。不同于其他激酶,，c-Met作為腫瘤信號(hào)網(wǎng)絡(luò)通路中的關(guān)鍵節(jié)點(diǎn)蛋白,，可以與細(xì)胞表面其他激酶、受體相互作用而備受關(guān)注,。特別是,，MET基因擴(kuò)增與20%的EGFR-TKIs獲得性耐藥密切相關(guān)，因此尋找新穎高效的c-Met抑制劑已成為醫(yī)藥界研究的前沿?zé)狳c(diǎn),。
上海藥物所藥物化學(xué)課題組和腫瘤藥理課題組研究人員通力合作,，通過(guò)合理的藥物設(shè)計(jì)和結(jié)構(gòu)優(yōu)化，發(fā)現(xiàn)了一類選擇性地靶向受體酪氨酸激酶c-Met的多取代喹啉衍生物,，其在分子水平對(duì)c-Met酶活抑制高達(dá)0.95 ± 0.13 nM,，與已報(bào)道的高活性化合物相當(dāng)。進(jìn)一步研究表明,，這類化合物對(duì)c-Met活化介導(dǎo)的下游關(guān)鍵信號(hào)通路以及c-Met依賴性腫瘤細(xì)胞株的增殖具有明顯的抑制作用,。同時(shí)，體內(nèi)結(jié)果顯示,，該化合物對(duì)HGF誘導(dǎo)的c-Met依賴性人神經(jīng)膠質(zhì)瘤U87-MG裸小鼠移植瘤和非HGF依賴性的NIH3T3/TPR-Met裸小鼠移植瘤的生長(zhǎng)均具有明顯的抑制作用,。 這一研究結(jié)果不僅為進(jìn)一步研究c-Met介導(dǎo)的生物功能提供了一類全新的分子探針，同時(shí)為開發(fā)具有我國(guó)自主知識(shí)產(chǎn)權(quán)抗腫瘤藥物提供了一類潛力較好的藥物先導(dǎo)物,。
研究成果最近發(fā)表在《Journal of Medicinal Chemistry》 (2011, 54：2127-2142)上,。文章發(fā)表第二天即收到美國(guó)Calbiochem公司要求購(gòu)買并商品化該產(chǎn)品的請(qǐng)求。同時(shí),，SciBX (The Science Business eXchange,， 是由Nature出版社推出的，以分析生命科學(xué)領(lǐng)域最具商業(yè)潛力的學(xué)術(shù)文獻(xiàn)為內(nèi)容的電子期刊) 也把這一工作作為本周新聞進(jìn)行報(bào)道（http://www.nature.com/scibx/journal/v4/n13/pdf/scibx.2011.363.pdf）,。（生物谷Bioon.com）
生物谷推薦原文出處：
J. Med. Chem., 2011, 54 (7), pp 2127–2142 DOI: 10.1021/jm101340q
Synthesis and c-Met Kinase Inhibition of 3,5-Disubstituted and 3,5,7-Trisubstituted Quinolines: Identification of 3-(4-Acetylpiperazin-
1-yl)-5-(3-nitrobenzylamino)-7- (trifluoromethyl)quinoline as a Novel Anticancer Agent
Yuanxiang Wang?, Jing Ai?, Ying Wang?, Yi Chen?, Lu Wang?, Gang Liu?, Meiyu Geng*?, and Ao Zhang*?
By use of an improved synthetic strategy, a series of 3,5-disubstituted and 3,5,7-trisubstituted quinolines were readily prepared. 3,5,7-Trisubstituted quinolines 21a?c, 21l, and 27a?c were identified as the most potent c-Met inhibitors with IC50 of less than 1.0 nM. Compound 21b showed the most promising overall PK profile and has high potency and extraordinary selectivity to c-Met against c-Met family member Ron and 12 other tyrosine kinases. It produced constitutive inhibition of c-Met phosphorylation in c-Met dependent cell lines. At doses of 100 mg/kg, compound 21b showed statistically significant tumor growth inhibition (68?69%) in both NIH-3T3-TPR-Met and U-87 MG human gliobastoma xenograft models. These results clearly indicated that compound 21b is a potent and highly selective c-Met inhibitor. Its favorable in vitro and in vivo profiles warrant further investigation.
