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Optimization of a novel class of microtubule stabilizers

一类新型微管稳定剂的优化

基本信息

批准号：
10380579
负责人：
April L Risinger
金额：
$ 34.4万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-17 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10380579
关键词：
ABCB1 gene ATP-Binding Cassette Transporters Adult Antineoplastic Agents Binding Binding Sites Biochemical Biological Markers Biotin Breast Cancer cell line Cell Line Clinical Crystallization Data Detection Development Drug Kinetics Drug resistance Effectiveness Evaluation Future Generations Goals In Vitro Laboratories Lead Mediating Metastatic breast cancer Microtubule Stabilization Microtubule stabilizing agent Microtubules Modeling Modification Molecular Multi-Drug Resistance Paclitaxel Patients Pharmaceutical Preparations Plants Property Resistance Signal Pathway Site Skeleton Solid Neoplasm Structure Tacca Testing Therapeutic Therapeutic Index Time Tubulin Tumor-Derived Vertebral column acquired drug resistance antitumor effect base beta Tubulin clinical development clinically relevant cytotoxic docetaxel drug-sensitive effective therapy follow-up improved in vivo in vivo Model insight lead candidate molecular marker next generation novel novel therapeutics patient derived xenograft model pharmacokinetics and pharmacodynamics pharmacophore predicting response rational design refractory cancer response response biomarker taxane triple-negative invasive breast carcinoma tumor tumor xenograft uptake

项目摘要

Microtubule stabilizing agents (MSAs) are some of the most widely used and effective therapies available for the treatment of solid tumors. However, their utility is compromised by innate and acquired drug resistance. The taccalonolides (taccas) are a mechanistically unique class of MSAs that circumvent multiple clinically relevant forms of drug resistance. Multiple potent taccas identified by our laboratories have effective antitumor activity in drug sensitive and resistant in vivo models but suffer from a narrow therapeutic window. This project will develop an in depth understanding of the pharmacokinetics and pharmacodynamics of this class of MSAs that will yield taccas with an optimal in vivo profile for future clinical development. The recent generation of a crystal structure of a tacca bound to tubulin heterodimers has provided unprecedented insight into the tacca pharmacophore, which will be used to experimentally define the critical residues on tubulin and moieties on the taccas that mediate their novel mechanism of microtubule stabilizing activity. We have also identified sites on the tacca skeleton that can be modified semi-synthetically to improve compound stability and optimize their pharmacokinetic profile and antitumor actions. Functional fluorescent and biotin-tagged taccas have been generated that will allow, for the first time, direct detection of the taccas in vitro and in vivo that will be instrumental in understanding the uptake, distribution, and target binding of this unique MSA. In addition to generating taccas with a more favorable pharmacokinetic profile and evaluating their efficacy in molecularly defined patient derived tumor xenograft and syngeneic models, we will also determine biomarkers associated with response to this novel class of MSAs. Expression analysis in a panel of molecularly defined triple negative breast cancer cell lines identified signaling pathways that correlate with the cytotoxic efficacy of the taccas. We will further evaluate whether intrinsic alterations in these signaling pathways are biomarkers of drug response and, reciprocally, follow up on data indicating that the taccas can also alter the functional consequences of these signaling pathways. These studies are significant in that they will lead, in the future, to the generation of a clinical lead candidate for the treatment of drug resistant solid tumors and a greater understanding of their mechanism of action and predictors of response.

微管稳定剂（MSA）是一些最广泛使用和有效的治疗方法用于治疗实体瘤。然而，它们的效用受到先天和后天药物的影响，阻力taccalonolides（taccas）是一类机械独特的MSA，多种临床相关形式的耐药性。我们的实验室鉴定出多种强效玉米粉在药物敏感和耐药的体内模型中具有有效的抗肿瘤活性，治疗窗口该项目将深入了解药物代谢动力学，这类MSA的药效学将产生具有最佳体内特征的塔卡斯，用于未来的研究。临床发展。与微管蛋白结合的塔卡晶体结构的最新一代异源二聚体提供了对塔卡药效团的前所未有的了解，这将用于通过实验确定了微管蛋白上的关键残基和介导其新的微管稳定活性的机制。我们还在塔卡骨架上发现了半合成修饰以改善化合物稳定性并优化其药代动力学特征和抗肿瘤作用。已经产生了功能性荧光和生物素标记的塔卡斯，第一次允许在体外和体内直接检测塔卡斯，这将有助于了解这种独特的MSA的摄取、分布和靶向结合。除了生成具有更有利的药代动力学特征的玉米片，并评估其在分子定义的患者来源的肿瘤异种移植物和同基因模型，我们还将确定相关的生物标志物，对这类新的MSA的反应。在一组分子定义的三联体中的表达分析阴性乳腺癌细胞系鉴定了与以下细胞毒性功效相关的信号传导途径：塔卡斯。我们将进一步评估这些信号通路中的内在改变是否是药物反应的生物标志物，并且，尽管如此，跟踪数据表明，玉米粉也可以改变这些信号通路的功能性后果。这些研究的重要性在于，在未来，导致产生用于治疗耐药固体的临床主要候选物，肿瘤和更好地了解他们的作用机制和预测反应。