Water Soluble Antimitotics That Circumvent Rumor Resistance

规避谣言抵抗的水溶性抗有丝分裂剂

基本信息

批准号：
8450879
负责人：
ALEEM GANGJEE
金额：
$ 29.49万
依托单位：
DUQUESNE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-06-01 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8450879
关键词：
ABCB1 gene Antimitotic Agents Antineoplastic Agents Binding Binding Sites Biological Biological Assay Biological Testing Cancer Model Cancer cell line Cancerous Cell Line Cells Clinic Clinical Colchicine Colon Carcinoma Development Digit structure Disease Resistance Drug Kinetics Drug resistance Epithelial Cells Evaluation Exhibits Failure Goals Health Sciences Hela Cells Human In Vitro Inhibitory Concentration 50 Ixabepilone Lead Letters Malignant Neoplasms Mediating Melanoma Cell Microtubule Depolymerization Microtubules Modeling Molecular Models Mus National Cancer Institute New Agents Normal Cell P-Glycoprotein Paclitaxel Patients Pharmaceutical Preparations Phase I Clinical Trials Plague Property Radiation Relative (related person)Renal carcinoma Resistance Salts Series Site Structure Taxane Compound Testing Texas Toxic effect Treatment Failure Tubulin Tumor Burden Tumor Cell Line Universities Vinca Vinca Alkaloids Water Xenograft Model Xenograft procedure analog anticancer activity antitumor agent base cancer therapy chemotherapy clinically relevant computational chemistry cytotoxicity follow-up in vivo inhibitor/antagonist malignant breast neoplasm meetings molecular modeling mouse model neoplastic cell novel overexpression pharmacophore resistance mechanism scaffold taxane tumor tumor xenograft water solubility

项目摘要

DESCRIPTION (provided by applicant): Though anitumor antimitotic agents are some of the most successful anticancer agents, such as taxanes, these agents are plagued by numerous drawbacks that are the cause of chemotherapy failure. In Preliminary Studies we have discovered a unique set of antitumor antimitotics that: 1) possess a broad spectrum of potent antitumor activity (60 tumor cell lines at nanomolar GI50); 2) circumvent tumor resistance due to overexpression of P-glycoprotein (MDR) and/or ?III-tubulin, two of the major clinically relevant tumor resistance mechanisms that hinder antitubule activity of the taxanes and other antimitotics; 3) are highly water soluble, thus overcome the lack of water solubility that continue to plague a large number of antimitotics including the newly approved ixabepilone; 4) are selective for tumor cells over normal cells; 5) bind to or near the colchicine-site in tubulin; and 6) are highly efficacious in tumor xenograft without toxicity. The analogs proposed for optimization of the lead compounds are easily synthesized as water soluble salts. The analogs will be evaluated as inhibitors of tumor cells and tubulin assembly in vitro and active compounds will be prioritized for further studies in three xenograft models and in Taxol resistant tumors in vivo murine tumor models. These results will allow the development of pharmacophores that will provide other molecules to be synthesized. The Specific Aims of this project are: 1) to synthesize and optimize the activities of lead compounds; 2) to evaluate the activities of the synthesized analogs as inhibitors of tumor cells in culture and of tubulin assembly and mechanistic studies; 3) to evaluate prioritized, selected analogs in vivo in sensitive and resistant murine tumor models. The broad long term goals of this project are to optimize these novel agents to allow the selection of a candidate or candidates for Phase I clinical trials as antitumor agent(s) to be used alone or in combination with other antitumor agents (including other antimitotics) as well as radiation for the treatment of a broad spectrum of cancers and to fill an unmet need for patients with antitubulin resistant diseases.

描述（由申请人提供）：尽管Anitumor Anitumor抗魔法剂是一些最成功的抗癌药，例如紫杉烷，但这些药物受到了造成化学疗法失败的原因的许多缺点。在初步研究中，我们发现了一组独特的抗肿瘤抗毒剂：1）具有广泛的有效抗肿瘤活性（纳摩尔GI50的60个肿瘤细胞系）； 2）由于P-糖蛋白（MDR）和/或？III-微管蛋白的过表达，抑制肿瘤耐药性，这是两种主要与临床相关的肿瘤耐药机制，它们阻碍了群群和其他抗毒剂的抗卵脂活性； 3）高度水溶性，因此克服了缺乏水溶性，这些水溶解度继续困扰着大量的抗毒剂，包括新认可的ixabepilone； 4）对正常细胞的肿瘤细胞有选择性； 5）在微管蛋白中与秋水仙碱部位结合；和6）在没有毒性的肿瘤异种移植物中高效。提出的用于优化铅化合物的类似物很容易合成为水溶性盐。类似物将被评估为在体外的肿瘤细胞和微管蛋白组装的抑制剂和活性化合物中，将优先在三种异种移植模型中进一步研究，并在体内鼠类肿瘤模型中的抗紫杉醇耐肿瘤中进行进一步研究。这些结果将允许开发药体，以提供其他分子合成。该项目的具体目的是：1）合成和优化铅化合物的活动； 2）评估合成类似物作为培养和微管蛋白组装和机械研究中肿瘤细胞抑制剂的活性； 3）为了评估优先级，在敏感和抗性鼠肿瘤模型中选择了体内的类似物。该项目的长期长期目标是优化这些新型药物，以允许选择候选者或候选者作为I临床试验作为抗肿瘤剂，作为抗肿瘤剂，或与其他抗肿瘤药物（包括其他抗虫剂）（包括其他抗毒剂）一起使用，以供抗药性和抗药性患者的范围内的患者进行抗衡的患者。