COMPUTER-AIDED DESIGN, SYNTHESIS, AND TESTING OF A NOVEL FAMILY OF TRIAZOLE-BASED

描述(申请人提供)：微管蛋白结合化合物干扰微管的动态稳定性，破坏有丝分裂纺锤体的形成，被广泛认为是最理想的抗癌药物之一。不幸的是，几乎所有临床上可用于人类癌症治疗的微管蛋白结合剂(紫杉醇、多西紫杉醇、长春新碱、长春花碱等)面临着严重的缺陷，包括神经毒性、最低的生物利用度和较差的溶解性、复杂的合成或分离程序，以及最重要的是产生抗药性。因此，迫切需要发现新的口服活性抗有丝分裂化合物来规避这些责任。利用计算机辅助药物设计策略，我们发现了一类新的以微管蛋白的秋水仙碱结合位点为靶点的1，3，4-三氮唑类小分子化合物。具有代表性的五个化合物在体外对所有亲本和多药耐药癌细胞株都显示出很强的微管蛋白聚合抑制活性和细胞毒性。这些化合物是低分子量(&lt；350)、易于合成、无手性和水溶性的化合物。这项第一阶段研究的总体目标是探索一系列扩大的基于三氮唑的微管蛋白抑制剂，作为潜在的用于癌症化疗的口服活性药物。为了实现这一目标，我们将采用一种综合策略，将虚拟合成和筛选、基于结构的药物设计、电子计算机ADME/Tox过滤、化学合成以及我们现有先导化合物T115的一系列新的基于三唑的结构类似物的生物表征相结合。这些被选择进行化学合成的化合物将在体外根据它们扰乱癌细胞周期和诱导细胞骨架解体的能力进行表征。我们将从我们的体外研究中挑选2-5个候选者进行体内疗效和毒性研究，使用小鼠模型。斯诺登已经组建了一支有能力的团队，在这个项目的各个方面都有相关的专业知识，以确保成功。公共卫生相关性：鉴于癌症导致的高死亡率和致残率，旨在发现癌症治疗新药的研究至关重要。基于我们现有的先导化合物T115已经在小鼠结直肠癌异种移植模型中显示出良好的体内活性，我们现在将探索一系列更广泛的基于三氮唑的T115类似物作为抗癌治疗药物。因此，这项拟议的研究将进行一项综合发现计划，该计划结合了计算机辅助设计以及对这些T115类似物的预定义系列进行计算机筛选、化学合成和生物学评估。

DESCRIPTION (provided by applicant): Tubulin binding compounds that interfere with the dynamic stability of microtubules and disrupt the formation of the mitotic spindle are widely considered one of the most desirable classes of anti-cancer agents. Unfortunately virtually all clinically available tubulin binding agents used for human cancer therapy (paclitaxel, docetaxel, vincristine, vinblastine, etc.) face severe drawbacks, including neurotoxicity, minimal bioavailability and poor solubility, complex synthesis or isolation procedures and, most importantly, the development of drug resistance. Therefore, there exists an urgent need for discovery of novel orally active anti-mitotic compounds that circumvent these liabilities. Employing computer-aided drug design strategies, we have discovered a novel family of 1,3,4-triazole-based small-molecule compounds that target the colchicine binding site of tubulin. A representative subset of five compounds exhibited strong in vitro tubulin polymerization inhibitory activity and cytotoxicity against all parental and multi-drug resistant cancer cell lines tested thus far. These compounds are low molecular weight (<350), easy to synthesize, achiral, and water soluble. The overall goal of this Phase I study is to explore an expanded series of these triazole-based tubulin inhibitors as potential orally active drugs for cancer chemotherapy. To achieve this goal, we will employ an integrated strategy that combines virtual synthesis & screening, structure-based drug design, in silico ADME/Tox filtering, chemical synthesis, and biological characterization of an expanded series of novel triazole-based structural analogs of our existing lead compound T115. Those compounds selected for chemical synthesis will be characterized in vitro in terms of their ability to disrupt the cancer cell cycle and induce cytoskeleton disorganization. We will select 2-5 candidates emanating from our in vitro studies for in vivo efficacy and toxicity studies using mouse models. Snowdon has assembled a capable team with relevant expertise in all aspects of this project to ensure success. PUBLIC HEALTH RELEVANCE: In view of the high rate of death and disability caused by cancer, research aimed at discovering new drugs for cancer treatment is critically important. Based on our existing lead compound T115 which has already demonstrated excellent in vivo activity in a mouse colorectal cancer xenograft model, we will now explore a broader series of triazole-based T115 analogs as antimitotic agents for cancer therapy. Consequently, the proposed study will pursue an integrated discovery program that combines computer-aided design and in silico screening, chemical synthesis, and biological evaluation of a pre-defined series of these T115 analogs.