Development of small molecule inhibitor of Mcl-1 for cancer treatment

开发用于癌症治疗的Mcl-1小分子抑制剂

基本信息

批准号：
8000762
负责人：
MICHAEL H CARDONE
金额：
$ 69.18万
依托单位：
EUTROPICS 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：
2008-06-16 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8000762
关键词：
Affinity Animals BH3 Domain Binding Biological Assay Boston Canis familiaris Cells Cellular biology Chicago Clinical Clinical Trials Companions Complex Computer Simulation Contracts Dana-Farber Cancer Institute Development Development Plans Diagnostic Diagnostic tests Drug Delivery Systems Drug Formulations Drug Kinetics Exhibits Family Funding Grant Hematologic Neoplasms In Vitro Inhibitory Concentration 50 Institutes Lead Lymphoid MCL1 protein Malignant Neoplasms Mitochondria Modeling Modification Molecular Molecular Bank Molecular Models Multiple Myeloma Mus Myelogenous Non-Hodgkin&apos s Lymphoma Oral Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacodynamics Pharmacologic Substance Pharmacology Pharmacology and Toxicology Phase Production Property Protein Family Proteins Protocols documentation Publishing Rattus Reporting Research Resolution Safety Science Screening procedure Series Small Business Innovation Research Grant Specificity Structure Structure-Activity Relationship United States National Institutes of Health Validation Work Xenograft Model Xenograft procedure analog anti-cancer therapeutic base cancer cell cancer therapy drug candidate drug discovery improved in vivo inhibitor/antagonist leukemia meetings member mimetics molecular modeling novel oncology phase 1 study protein protein interaction public health relevance scaffold small molecule small molecule libraries therapeutic target tumor

项目摘要

DESCRIPTION (provided by applicant): The Bcl-2 family proteins are key effectors of cancers. Recent studies indicate that Myeloma cell factor-1 (Mcl-1), a member of this protein family, is a key regulator of lymphoid cancers including Multiple Myeloma (MM), Non-Hodgkin's Lymphoma (NHL), and other cancers. Mcl-1 is regulated by distinct protein-protein interactions. Manipulation of these interactions using compounds that mimic the crucial binding domain, the BH3 domain, is a valid approach to developing oncology drugs. Efforts by commercial and academic groups have yielded several classes of compounds that target certain members of the Bcl-2 family. To date however, there has been no successful effort to develop a drug that targets Mcl-1. There is a clear unmet need for such a drug. In this application we propose the continued development of a novel compound that is highly active against Mcl-1. In our phase 1 study we identified a lead compound, characterized its in vitro and in vivo on-target activity, and demonstrated efficacy in a mouse xenograft model. We are now proceeding with a comprehensive med chem. optimization strategy that utilizes NMR analysis, computational modeling, and a novel mitochondrial assay that guide development of an IND candidate. We will also incorporate results from a small molecule library screen performed with The Scripps Institute Molecular Screening Center (TSIMSC) under a grant from the NIH Molecular Libraries Probe Center Network (MLPCN) to help further guide SAR and provide potential backup compounds. . Eutropics has assembled a highly competent team that is operating in our facility in Boston, MA. We have the active participation of SAB members Gerhard Wagner, Anthony Letai, and Ed Roberts, contributing expertise in, structural pharmacology, cancer cell biology/oncology, and translational medicinal chemistry. PUBLIC HEALTH RELEVANCE: Eutropics has assembled a strong science team further develop an anti-cancer therapeutic that targets the myeloid factor-1(Mcl-1) protein. Mcl-1 has been shown to be causal in certain cancers and is highly regarded as a drug target. In our SBIR phase I study we followed a plan to develop structure activity relationship (SAR) of early compounds and have identified a new lead compound. Our lead compound has activity against the target protein that is ten-fold more active than any such compounds reported. In vitro and in vivo studies support the development of this compound as a drug for treating multiple myeloma and other cancers. We describe our progress and plans for going forward, and we propose that this important work continue with SBIR phase II funding.

描述（由申请人提供）：Bcl-2家族蛋白是癌症的关键效应子。最近的研究表明，该蛋白质家族的成员是骨髓瘤细胞因子1（MCL-1），是包括多种骨髓瘤（MM），非霍奇金淋巴瘤（NHL）和其他癌症在内的淋巴癌的关键调节剂。 MCL-1受不同蛋白质蛋白相互作用的调节。使用模仿关键结合结构域BH3结构域的化合物对这些相互作用进行操纵，是开发肿瘤药物的有效方法。商业和学术团体的努力产生了针对BCL-2家族某些成员的几类化合物。但是，迄今为止，还没有成功开发针对MCL-1的药物的努力。这种药物明显未满足。在此应用中，我们提出了一种对MCL-1高度活跃的新型化合物的持续开发。在我们的第一阶段研究中，我们确定了铅化合物，表征了其体外和体内靶向活性，并在小鼠异种移植模型中证明了功效。我们现在正在进行全面的药物化学。利用NMR分析，计算建模和新型线粒体测定的优化策略，该测定指导IND候选者的开发。我们还将在NIH分子库探测中心网络（MLPCN）的赠款下，将使用Scripps Institute分子筛选中心（TSIMSC）进行的小分子库筛选的结果结合起来，以帮助进一步指导SAR并提供潜在的备份化合物。。 Eutropics已组建了一支在马萨诸塞州波士顿的工厂运营的高能力的团队。我们有SAB成员Gerhard Wagner，Anthony Letai和Ed Roberts的积极参与，在结构药理学，癌细胞生物学/肿瘤学和转化药物化学方面贡献了专业知识。公共卫生相关性：Eutropics汇集了一个强大的科学团队，进一步开发了一种靶向髓样因子1（MCL-1）蛋白质的抗癌治疗。 MCL-1在某些癌症中已被证明是因果关系，被高度视为药物靶标。在我们的SBIR I期研究中，我们遵循了一项计划，以开发早期化合物的结构活动关系（SAR），并确定了一种新的铅化合物。我们的铅化合物具有针对靶蛋白的活性，其活性比任何报道的任何此类化合物都要高十倍。体外和体内研究支持这种化合物作为治疗多发性骨髓瘤和其他癌症的药物的发展。我们描述了我们未来的进步和计划，我们建议SBIR II阶段资金继续进行这项重要工作。