Screening of drugs that suppress Ste11 MAPKKK activation in yeast identified a c-Abl tyrosine kinase inhibitor
Screening of drugs that suppress Ste11 MAPKKK activation in yeast identified a c-Abl tyrosine kinase inhibitor
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DOI：
10.1271/bbb.60610
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发表时间：
2007-03-01
影响因子：
1.6
通讯作者：
Akada, Rinji
中科院分区：
文献类型：
--
作者：
Kitagawa, Takao;Hashizume, Yuko;Akada, Rinji
酵母MAPKKK Ste 11激活三种MAP激酶途径，包括信息素信号传导、生物传感和假菌丝/侵入生长途径。我们确定了两种化合物，BTB 03006和GK 03225，可以抑制二倍体酵母细胞中由Ste 11激活诱导的生长缺陷。发现BTB 03006而不是GK 03225抑制由信息素信号传导途径中的α-因子和Ste 4 G（β）过表达诱导的生长缺陷，表明GK 03225是一种α-因子敏感途径特异性抑制剂。我们还进行了全基因组抑制分析的Ste 11激活，使用酵母缺失菌株收集，并确定了PBS 2和HOG 1，和几个基因与伴侣蛋白功能，这代表潜在的靶蛋白的药物筛选从Ste 11激活。GK 03225具有Iressa样喹唑啉环结构，其化学类似物11 N-078抑制c-Abl人酪氨酸激酶活性。这些结果表明，在酵母中的药物筛选可以识别人类酪氨酸激酶抑制剂和其他药物的人类疾病。
The yeast MAPKKK Ste11 activates three MAP kinase pathways, including pheromone signaling, osmo-sensing, and pseudohyphal/invasive growth pathways. We identified two chemical compounds, BTB03006 and GK03225, that suppress growth defects induced by Ste11 activation in diploid yeast cells. BTB03006, but not GK03225, was found to suppress growth defects induced by both a-factor and Ste4 G(beta) overexpression in the pheromone signaling pathway, suggesting that GK03225 is an osmosensing pathway-specific inhibitor. We also performed genome-wide suppressor analysis for Ste11 activation, using a yeast deletion strains collection, and identified PBS2 and HOG1, and several genes associated with chaperone functions, which represent potential target proteins of the drugs screened from Ste11 activation. GK03225 possesses an Iressa-like quinazoline ring structure, and its chemical analog, 11N-078, suppresses c-Abl human tyrosine kinase activity. These results suggest that drug screening in yeast can identify human tyrosine kinase inhibitors and other drugs for human diseases.