Water Soluble Antimitotics That Circumvent Rumor Resistance

描述(申请人提供)：虽然抗肿瘤抗分裂药物是最成功的抗癌药物，如紫杉烷，但这些药物有许多缺点，是导致化疗失败的原因。在初步研究中，我们发现了一组独特的抗肿瘤药物：1)具有广泛的有效抗肿瘤活性(60个肿瘤细胞株在纳米分子GI50)；2)由于P-糖蛋白(MDR)和/或？III-微管蛋白的过度表达而绕过肿瘤耐药，这是两种主要的临床相关肿瘤耐药机制，阻碍紫杉烷和其他抗肿瘤药物的抗小管活性；3)高度水溶性，从而克服了继续困扰包括新批准的ixabpione在内的大量抗癌药物的缺乏水的问题；4)对肿瘤细胞具有选择性；5)结合或靠近秋水仙碱-微管蛋白；和6)在无毒性的肿瘤异种移植中高效。所提出的用于优化先导化合物的类似物很容易合成为水溶性盐。这些类似物将在体外作为肿瘤细胞和微管组装的抑制剂进行评估，活性化合物将优先用于三种异种移植模型和体内小鼠肿瘤模型的紫杉醇耐药肿瘤的进一步研究。这些结果将使药效团的开发成为可能，这些药效团将提供其他待合成的分子。本项目的具体目标是：1)合成和优化先导化合物的活性；2)评估合成的类似物在培养中作为肿瘤细胞抑制剂的活性以及微管蛋白组装和机制研究；3)在敏感和耐药的小鼠肿瘤模型中评估优先选择的类似物。该项目广泛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(S)单独使用或与其他抗肿瘤药物(包括其他抗肿瘤药物)以及放射治疗联合使用，用于治疗多种癌症，并填补抗微管蛋白耐药性疾病患者尚未满足的需求。

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.