标题: | 分子间药理作用介面家族应用在磷酸化酵素-药物-疾病网络与机制之研究 Molecular Pharma-interface Families for Kinase-drug-disease Network and Mechanisms |
作者: | 杨进木 Jinn-Moon Yang 国立交通大学生物科技研究所 |
关键字: | 分子间药理作用介面家族;旧药新用;多标的药物;磷酸化酵素;癌症治疗;副作用;Molecular pharma-interface family;New uses for old drugs;Multi-target drugs;Kinase;Cancer treatment;Side effect |
公开日期: | 2015 |
摘要: | 利用所提出之新概念“分子间药理作用介面家族(molecular pharma-interface family)”结合“区域官能基地图(site-moiety map, SiMMap)”,以探讨蛋白磷酸化酵素抑制剂之结合机制与选择性是本五年期计划的主要目标,并希望达成: (一)为上市药物与中草药寻找新用途(旧药新用)。(二)发展多标靶药物 (multi-target drugs)。(三)建立国人常见癌症之磷酸化酵素-药物-疾病关联性网络资料库,相信能藉此达到加速药物发展及增进治疗复杂疾病之效果。在前期(第四年)中我们已将相关成果发表于BMC Genomics (影响系数: 4.04) 与PLOS ONE (修订中,影响系数: 3.53),并于2014国际生物资讯研讨会 (International Conference on Bioinformatics 2014)口头报告两篇论文,其中一篇获得最佳论文奖,是国内少见的殊荣。另外,尚有一篇论文规划投稿中及一个美国专利申请中。 前期中我们完成了以下事项:(一)提出“同源药理(Homopharma)”概念,可用于旧药新用与副作用预测,并据此扩大草药-天然物-作用蛋白质-疾病(症状) 网路。(二)成功从旧有作为抗生素的药物中,发现可作为蛋白磷酸化酵素抑制剂的JMY104 [专利规划中],可专一性抑制表皮生长因子受体EGFR与第一型介白素受体之第四号相关激酶IRAK4,并扩大其使用范围:抗发炎功效筛选的实验证实,JMY104能有效抑制 (IC50 < 10 μM) NO及IL-6等发炎因子的产生;侵袭试验 (invasion assay) 结果显示,JMY104能有效抑制(IC50 ≈ 1.6 μM)恶性乳癌细胞MDA-MB-231的侵袭;细胞病变作用试验 (cytopathic effect assay) 结果显示,JMY104在高浓度时 (50 μM) 可抑制登革病毒 (DENV-2) 的复制。(三) 以广效型蛋白磷酸化酵素抑制剂为基础,藉由触及下游蛋白受质辨识锚点而创造S型选择性抑制剂(type S inhibitors),成为继以类黄酮为核心之后的另一类蛋白磷酸化酵素活化与否的开关[美国专利申请中]。已设计出18种S型选择性抑制剂,并进行大规模蛋白磷酸化酵素抑制活性分析,结果显示特定S型选择性抑制剂可将选择性由>90%降至<2%,证实此概念的可行性,并有助于厘清蛋白磷酸化酵素抑制剂的选择性机制与探讨人类为何需要高达518种蛋白磷酸化酵素。(四)在过去的学术研究与产学合作的基础上,我们获得了科技部‘产学技术联盟合作计画 (产学小联盟)’的肯定与补助,成立生技及医药服务平台于生技产品开发联盟,提供五大服务: (1)中草药开发;(2)新药开发/旧药新用;(3)药物包覆及传输系统;(4)疾病检验暨中草药功效分析基因晶片试剂套组;(5) 蛋白质酵素/细胞实验。并成功举办“2014 生技及医药应用平台: 新药开发-健康食品-医药检测 产学联盟研讨会”,吸引152人次与20间厂商与会。与葡萄王生技、华联生技、景凯生技、奎克生技等厂商签约,共同合作开发产品。 上述研究成果已达到计画去年之预期目标,初步成果显示“同源药理”的概念是可行的,并成功找出JMY104抗生素作为选择性蛋白磷酸化酵素抑制剂,扩大其应用范围至抗发炎、抗癌症转移与抗登革等领域。而S型选择性抑制剂的开发则有助于探讨蛋白磷酸化酵素抑制剂的选择性机制与人类为何需要高达518种蛋白磷酸化酵素。本年度的工作构想,主要分为三大部分:(一)将蛋白磷酸化酵素由人类扩展至常见致病菌株,以开发新型抗生素。(二)优化S型选择性抑制剂,并找出其潜在医疗标的。(三)中草药药理平台是以系统生物学的方式为中草药的疗效提出科学化的解释,而将其网路服务化,则使学者与一般民众对中草药的作用机理能有更进一步的认识,达到教育普及的目的。 The addressed issue of this project is to explore the binding mechanisms and kinase inhibitor selectivity by the novel concept, molecular pharma-interface family, and site-moiety map (SiMMap). There are three goal of this project including (1) new usages or targets of approved drugs and the Chinese herbs; (2) developments of multi-target drugs; (3) for popular diseases (such as cancers), to build the kinase-drug-disease network. It would be helpful to increase the drug developments and therapeutic effects of complex diseases. In previous period (fourth year), we have published 2 scientific papers (BMC Genomics, impact factor: 4.04; PLOS ONE, impact factor: 3.53), oral presented 2 papers at International Conference on Bioinformatics 2014, and one of them got the Best Paper Award. In addition, we have one submitted paper and one applied U.S.A patent. During the period, we first proposed the “Homopharma” concept for new uses of existing drugs and side-effect prediction. Moreover, we applied “Homopharma” to extend the current kinase-drug-disease network to herb-natural product-target protein-disease network. And we identified an antibiotics JMY104 as a protein kinase inhibitor. Through kinase profiling assays, JMY104 can selectively inhibit EGFR and IRAK4. For expending the indications of JMY104, we performed several assays that EGFR and IRAK4 involved in. For example, we discovered JMY104 can reduce (IC50 < 10 μM) the inflammatory factor production of NO and IL-6 by anti-inflammation assays; inhibit (IC50 ≈ 1.6 μM) MDA-MB-231 malignant breast tumor cell line invasion by invasion assays; disturb dengue virus infection through cytopathic effect assay. In addition, we developed selective type S inhibitors based on promiscuous protein kinase inhibitor staurosporine through targeting substrate recognition pocket for protein kinase switching. Through large scale kinase profiling for 18 developed type S inhibitors, we discovered the inhibitor selectivity can be significantly reduced from > 90% to < 2%. These results supported our hypothesis that substrate site is critical for inhibitor selectivity and were helpful for exploring inhibitor selectivity mechanisms and why human need 518 protein kinases. Furthermore, according to the academic and industrial results, we got the financial supports from “University-Industry Technology Alliance Program” of Ministry of Science and Technology. And we constructed the platform for integrating the resources between academia and industry for product development. In addition, we provides related services and consultation for industry, such as drug development, new uses for existing drugs and herbs, drug delivery, bio-marker identification, diagnostic kits, enzymatic assays and cell-based assays. Moreover, we successfully held the conference on drug development, health food, diagnosis at National Chiao Tung University and joined over 152 participants and 20 biotech companies. These results achieved the anticipated goals and showed that “Homopharma” is efficient for new uses for existing drugs. In addition, identified an antibiotics JMY104 as a selective EGFR and IRAK4 protein kinase inhibitor with anti-inflammation, anti-tumor metastasis and anti-dengue potentials. And type S inhibitors were helpful for kinase inhibitor selectivity mechanisms and exploring why human need 518 protein kinases. The goals of this year are described as following: (1) Develop novel antibiotics by targeting protein kinases in bacteria. (2) Identify new indications for type S inhibitors. (3) Provide the web services about “Herb-natural product-target protein-disease network.” |
官方说明文件#: | NHRI-EX104-10009PI |
URI: | http://hdl.handle.net/11536/130434 https://www.grb.gov.tw/search/planDetail?id=8438219&docId=451874 |
显示于类别: | Research Plans |