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

描述（由申请人提供）：Bcl-2家族蛋白是癌症的关键效应物。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（包括多发性骨髓瘤（MM）、非霍奇金淋巴瘤（NHL）和其他癌症）的关键调节因子。 Mcl-1受不同的蛋白质-蛋白质相互作用调节。使用模拟关键结合结构域BH 3结构域的化合物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，还没有成功的努力来开发靶向Mcl-1的药物。对这种药物的需求显然没有得到满足。 在本申请中，我们建议继续开发对Mcl-1具有高活性的新型化合物。在我们的1期研究中，我们鉴定了一种先导化合物，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疗效。 我们现在正在进行一项全面的药物化学优化策略，该策略利用NMR分析、计算建模和一种新型线粒体测定来指导IND候选药物的开发。我们还将在NIH分子库探针中心网络（MLPCN）的资助下，与斯克里普斯研究所分子筛选中心（TSIMSC）进行小分子库筛选，以帮助进一步指导SAR并提供潜在的备用化合物。. Eutropics已经组建了一支非常称职的团队，在我们位于马萨诸塞州波士顿的工厂工作。SAB成员Gerhard瓦格纳、Anthony Letai和艾德罗伯茨积极参与，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组建了一支强大的科学团队，进一步开发了一种针对髓样因子-1（Mcl-1）蛋白的抗癌治疗药物。Mcl-1已被证明是某些癌症的病因，并被高度视为药物靶点。在我们的SBIR第一阶段的研究中，我们遵循了一个计划，开发早期化合物的结构活性关系（SAR），并确定了一个新的先导化合物。我们的先导化合物对靶蛋白的活性是任何此类化合物报道的10倍。体外和体内研究支持将该化合物开发为治疗多发性骨髓瘤和其他癌症的药物。我们描述了我们的进展情况和未来计划，我们建议在SBIR第二阶段资助下继续这项重要工作。

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.