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

基于三唑的新型家族的计算机辅助设计、合成和测试

基本信息

批准号：
7481409
负责人：
RICHARD D WOOD
金额：
$ 12.3万
依托单位：
SNOWDON PHARMACEUTICALS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-05-01 至 2010-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7481409
关键词：
Affect African Antimitotic Agents Antineoplastic Agents Binding Binding Sites Biochemical Biological Biological Assay Biological Availability Biological Factors Blood Vessels Breast Cancer cell line Cell Cycle Cell Line Cervical Chemotherapy-Oncologic Procedure Class Classification Clinical Trials Colchicine Colorectal Colorectal Cancer Colorectal Neoplasms Combretastatin Combretastatin A-4 Combretum Complex Computer Assisted Computer Simulation Computer-Aided Design Cytoskeleton Death Rate Development Docetaxel/Vincristine Drug Design Drug resistance Ensure Evaluation Exhibits Face Family Goals Growth Human In Vitro Lead Licensing Lung Malignant Neoplasms Malignant neoplasm of prostate Mammalian Cell Metabolic Microtubule Polymerization Microtubules Mitotic Mitotic spindle Modeling Molecular Weight Multi-Drug Resistance Mus Normal Cell Object Attachment Oral Ovarian Paclitaxel Permeability Pharmaceutical Preparations Pharmacologic Substance Phase I Clinical Trials Phase II Clinical Trials Procedures Prodrugs Property Prostate Public Health Publications Range Reporting Roentgen Rays Screening procedure Series Solubility Structure Testing Toxic effect Trees Triazoles Tubulin Tubulin Binding Agent Tumor Angiogenesis Vinblastine Vincristine Vinorelbine Virtual Library Water Willow Xenograft Model analog anticancer activity anticancer research aqueous base cancer cell cancer therapy cancer type chemical synthesis cytotoxicity disability docetaxel in vitro Assay in vivo inhibitor/antagonist inorganic phosphate leukemia mouse model neurotoxicity novel polymerization pre-clinical programs prospective racemization small molecule success tissue culture tumor virtual

项目摘要

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.

描述（由申请人提供）：干扰微管动态稳定性并破坏有丝分裂纺锤体形成的微管蛋白结合化合物被广泛认为是最理想的一类抗癌剂。不幸的是，几乎所有用于人类癌症治疗的临床上可用的微管蛋白结合剂（紫杉醇、多西紫杉醇、长春新碱、长春花碱等）都面临着严重的缺点，包括神经毒性、生物利用度极低和溶解度差、合成或分离过程复杂，最重要的是，开发的耐药性。因此，迫切需要发现新型口服活性抗有丝分裂化合物来规避这些缺点。采用计算机辅助药物设计策略，我们发现了一个新的基于 1,3,4-三唑的小分子化合物家族，其靶向微管蛋白的秋水仙碱结合位点。五种化合物的代表性子集对迄今为止测试的所有亲本和多重耐药癌细胞系表现出强大的体外微管蛋白聚合抑制活性和细胞毒性。这些化合物分子量低（<350）、易于合成、非手性且水溶性。这项 I 期研究的总体目标是探索这些基于三唑的微管蛋白抑制剂的扩展系列，作为癌症化疗的潜在口服活性药物。为了实现这一目标，我们将采用综合策略，结合虚拟合成和筛选、基于结构的药物设计、计算机 ADME/Tox 过滤、化学合成和我们的一系列新型基于三唑的结构类似物的生物表征。现有先导化合物T115。选择用于化学合成的那些化合物将在体外表征其破坏癌细胞周期和诱导细胞骨架解体的能力。我们将选择 2-5 个来自体外研究的候选药物，使用小鼠模型进行体内功效和毒性研究。斯诺登组建了一支精干的团队，在该项目的各个方面都具备相关专业知识，以确保项目的成功。公共健康相关性：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（已在小鼠结直肠癌异种移植模型中表现出优异的体内活性），我们现在将探索更广泛的系列基于三唑的 T115 类似物作为癌症治疗的抗有丝分裂剂。因此，拟议的研究将寻求一个综合的发现计划，该计划将计算机辅助设计与计算机辅助筛选、化学合成以及对这些 T115 类似物的预定义系列的生物学评估相结合。