Water Soluble Antimitotics That Circumvent Rumor Resistance

描述（由申请人提供）：虽然抗肿瘤抗有丝分裂剂是一些最成功的抗癌剂，如紫杉烷类，但这些药物受到许多缺点的困扰，这些缺点是化疗失败的原因。在初步研究中，我们发现了一组独特的抗肿瘤抗有丝分裂剂：1）具有广谱有效的抗肿瘤活性（60肿瘤细胞系在纳摩尔GI 50）; 2）规避肿瘤耐药由于过度表达的P-糖蛋白（MDR）和/或？III-微管蛋白，两种主要的临床相关的肿瘤抗性机制，其阻碍紫杉烷和其它抗有丝分裂剂的抗微管活性; 3）是高度水溶性的，因此克服了水溶性的缺乏，所述水溶性的缺乏继续困扰大量的抗有丝分裂剂，包括新批准的伊沙匹隆; 4）对肿瘤细胞的选择性超过正常细胞; 5）结合到微管蛋白中的秋水仙碱位点或其附近;和6）在肿瘤异种移植物中高度有效而无毒性。为优化先导化合物而提出的类似物易于合成为水溶性盐。类似物将在体外作为肿瘤细胞和微管蛋白组装的抑制剂进行评价，并且活性化合物将优先用于在三种异种移植模型和体内鼠肿瘤模型中的紫杉醇耐药肿瘤中的进一步研究。这些结果将允许开发药效团，从而提供其他待合成的分子。本项目的具体目的是：1）合成和优化先导化合物的活性; 2）评价合成的类似物作为培养中的肿瘤细胞抑制剂和微管蛋白组装和机制研究的活性; 3）在敏感和耐药小鼠肿瘤模型中评价优先选择的类似物。该项目的广泛长期目标是优化这些新型药物，以允许选择I期临床试验的一种或多种候选药物作为抗肿瘤药物，单独使用或与其他抗肿瘤药物（包括其他抗有丝分裂剂）以及放射联合使用，用于治疗广谱癌症，并满足抗微管蛋白耐药疾病患者的未满足需求。

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.