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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）：尽管肿瘤抗有丝分裂药物是一些最成功的抗癌药物，如紫杉烷，但这些药物受到许多缺陷的困扰，这些缺陷是化疗失败的原因。在初步研究中，我们发现了一套独特的抗肿瘤抗有丝剂：1)具有广谱的有效抗肿瘤活性（60个肿瘤细胞系在纳米摩尔GI50）；2)由于p -糖蛋白（MDR）的过度表达和/或？iii -微管蛋白，两种主要的临床相关肿瘤耐药机制，阻碍紫杉烷和其他抗有丝药物的抗小管活性；3)高水溶性，从而克服了继续困扰大量抗有丝分裂药物（包括新批准的伊沙匹龙）的水溶性不足；4)对肿瘤细胞比正常细胞有选择性；5)结合或靠近微管蛋白的秋水仙碱位点；6)对异种肿瘤移植有效，无毒性。提出的优化先导化合物的类似物很容易以水溶性盐的形式合成。这些类似物将被评估为肿瘤细胞和微管蛋白组装的体外抑制剂，活性化合物将优先用于三种异种移植模型和紫杉醇耐药肿瘤的体内小鼠肿瘤模型的进一步研究。这些结果将促进药效团的发展，从而提供其他分子的合成。本课题的具体目的是：1)合成并优化先导化合物的活性；2)评价合成的类似物作为肿瘤细胞培养和微管蛋白组装抑制剂的活性和机制研究；3)在敏感和耐药小鼠肿瘤模型中评估优先选择的体内类似物。该项目的长期目标是优化这些新型药物，以便选择一种或多种候选药物进行I期临床试验，作为抗肿瘤药物单独使用或与其他抗肿瘤药物（包括其他抗有核药物）联合使用，以及用于治疗广谱癌症的放射治疗，并填补抗微管蛋白耐药疾病患者的未满足需求。