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

• 批准号: 8224293
• 负责人: MICHAEL H CARDONE
• 金额: $ 32.2万
• 依托单位: EUTROPICS PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 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/8224293
• 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; Malignant Neoplasms; Mitochondria; Modeling; Modification; Molecular; Molecular Bank; Molecular Models; Multiple Myeloma; Mus; Myelogenous; Non-Hodgkin' 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; Study models; 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

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，骨髓瘤细胞因子 1 (Mcl-1) 是该蛋白家族的成员，是淋巴癌的关键调节因子，包括多发性骨髓瘤 (MM)、非霍奇金淋巴瘤 (NHL) 和其他癌症。 Mcl-1 受不同的蛋白质-蛋白质相互作用的调节。使用模拟关键结合域（BH3 结构域）的化合物来操纵这些相互作用是开发肿瘤药物的有效方法。商业和学术团体的努力已经产生了几类针对 Bcl-2 家族某些成员的化合物。然而迄今为止，尚未成功开发出针对 Mcl-1 的药物。对这种药物的需求显然尚未得到满足。 在此应用中，我们建议继续开发一种对 Mcl-1 具有高度活性的新型化合物。在我们的第一阶段研究中，我们鉴定了一种先导化合物，表征了其体外和体内的靶向活性，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医疗化学治疗。优化策略，利用 NMR 分析、计算模型和新型线粒体测定来指导 IND 候选药物的开发。我们还将整合斯克里普斯研究所分子筛选中心 (TSIMSC) 在 NIH 分子库探针中心网络 (MLPCN) 资助下进行的小分子库筛选结果，以帮助进一步指导 SAR 并提供潜在的备用化合物。 。 Eutropics 组建了一支高素质的团队，在我们位于马萨诸塞州波士顿的工厂中运营。 SAB 成员 Gerhard Wagner、Anthony Letai 和 Ed Roberts 积极参与，贡献了结构药理学、癌细胞生物学/肿瘤学和转化药物化学方面的专业知识。 公共健康相关性：Eutropics 组建了一支强大的科学团队，进一步开发一种针对髓样因子 1 (Mcl-1) 蛋白的抗癌疗法。 Mcl-1 已被证明与某些癌症有关，并被高度视为药物靶点。在我们的 SBIR 第一阶段研究中，我们遵循了开发早期化合物的结构活性关系 (SAR) 的计划，并确定了一种新的先导化合物。我们的先导化合物对目标蛋白的活性比报道的任何此类化合物的活性高十倍。体外和体内研究支持该化合物作为治疗多发性骨髓瘤和其他癌症的药物的开发。我们描述了我们的进展和未来的计划，并建议在 SBIR 第二阶段资金的支持下继续这项重要的工作。