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

描述(申请人提供)：Bcl2家族蛋白是癌症的关键效应因子。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，是多发性骨髓瘤(MM)、非霍奇金淋巴瘤(NHL)等淋巴系肿瘤的关键调节因子。MCL-1受不同的蛋白质-蛋白质相互作用调节。使用模仿关键结合结构域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，到目前为止，还没有成功的努力来开发针对Mcl-1的药物。显然，对这种药物的需求尚未得到满足。在本申请中，我们建议继续开发一种对Mcl-1具有高度活性的新化合物。在我们的第一阶段研究中，我们确定了一种先导化合物，表征了它在体外和体内的靶向活性，并在小鼠异种移植模型中展示了疗效。我们现在正在进行一项全面的医疗化学。优化策略，利用核磁共振分析、计算建模和一种新的线粒体检测来指导IND候选的开发。我们还将结合与斯克里普斯研究所分子筛选中心(TSIMSC)一起进行的小分子文库筛选的结果，这是由NIH分子文库探测中心网络(MLPCN)提供的赠款，以帮助进一步指导SAR并提供潜在的备用化合物。。Eutroics已经组建了一支能力很强的团队，在我们位于马萨诸塞州波士顿的工厂运营。我们有SAB成员Gerhard Wagner、Anthony Letai和Ed Roberts的积极参与，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。 公共卫生相关性：优生公司已经组建了一个强大的科学团队，进一步开发了一种针对髓系因子-1(Mcl-1)蛋白的抗癌疗法。MCL-1已被证明在某些癌症中具有因果关系，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构效关系(SAR)的计划，并鉴定了一种新的先导化合物。我们的先导化合物具有对抗目标蛋白的活性，其活性是报道的任何此类化合物的十倍。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和今后的计划，我们建议这项重要的工作继续使用SBIR第二阶段的资金。

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.