An in vivo large-scale chemical screening platform using Drosophila for anti-cancer drug discovery.
An in vivo large-scale chemical screening platform using Drosophila for anti-cancer drug discovery.
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DOI：
10.1242/dmm.009985
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发表时间：
2013-03
影响因子：
4.3
通讯作者：
Brumby AM
中科院分区：
文献类型：
--
作者：
Willoughby LF;Schlosser T;Manning SA;Parisot JP;Street IP;Richardson HE;Humbert PO;Brumby AM
抗癌药物的开发涉及巨大的支出和风险。为了快速、经济地鉴定新型、生物可利用的抗肿瘤化学物质，使用适合大规模筛选的适当体内肿瘤模型是关键。使用果蝇Ras驱动的肿瘤模型，我们证明可以通过给幼虫喂食化学物质来抑制肿瘤过度生长，这些化学物质具有药物开发所必需的体内药代动力学和已知的针对人类肿瘤细胞的功效。然后，我们开发了体内96孔板化学筛选平台，以肿瘤模型进行大规模化学筛选。在对 2000 种化合物进行原理验证试点筛选中，我们鉴定出谷氨酰胺类似物阿西维星（一种已知具有抗人类肿瘤细胞活性的化学物质）作为果蝇肿瘤形成的有效且特异性的抑制剂。 RNAi 介导的候选阿西维星靶基因的敲低表明参与嘧啶生物合成的酶 CTP 合酶可能是阿西维星介导的抑制的关键目标。因此，试点筛选表明，果蝇肿瘤是谷氨酰胺依赖性的，这是许多人类癌症的一个新特征，并验证了该平台作为体内化学筛选的强大而经济的工具。该平台还可以适用于其他疾病模型，从而在药物开发中提供广泛的应用。
Anti-cancer drug development involves enormous expenditure and risk. For rapid and economical identification of novel, bioavailable anti-tumour chemicals, the use of appropriate in vivo tumour models suitable for large-scale screening is key. Using a Drosophila Ras-driven tumour model, we demonstrate that tumour overgrowth can be curtailed by feeding larvae with chemicals that have the in vivo pharmacokinetics essential for drug development and known efficacy against human tumour cells. We then develop an in vivo 96-well plate chemical screening platform to carry out large-scale chemical screening with the tumour model. In a proof-of-principle pilot screen of 2000 compounds, we identify the glutamine analogue, acivicin, a chemical with known activity against human tumour cells, as a potent and specific inhibitor of Drosophila tumour formation. RNAi-mediated knockdown of candidate acivicin target genes implicates an enzyme involved in pyrimidine biosynthesis, CTP synthase, as a possible crucial target of acivicin-mediated inhibition. Thus, the pilot screen has revealed that Drosophila tumours are glutamine-dependent, which is an emerging feature of many human cancers, and has validated the platform as a powerful and economical tool for in vivo chemical screening. The platform can also be adapted for use with other disease models, thus offering widespread applications in drug development.
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影响因子：
16.2
作者：
McBride, SMJ;Choi, CH;Jongens, TA
通讯作者：
Jongens, TA
影响因子：
4.3
作者：
Pastor-Pareja, Jose Carlos;Wu, Ming;Xu, Tian
通讯作者：
Xu, Tian
影响因子：
4.1
作者：
Shah, Sheetal;Yarrow, Carol;Hadfield, Stephen
通讯作者：
Hadfield, Stephen
影响因子：
64.8
作者：
Dar, Arvin C.;Das, Tirtha K.;Shokat, Kevan M.;Cagan, Ross L.
通讯作者：
Cagan, Ross L.
影响因子：
14.8
作者：
Chang, Shuang;Bray, Steven M.;Warren, Stephen T.
通讯作者：
Warren, Stephen T.