Development of small molecule inhibitors of Mcl-1 for cancer treament

描述（由申请人提供）：Bcl-2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）是该蛋白家族的一员，是淋巴细胞癌包括b细胞淋巴瘤、多发性骨髓瘤和慢性淋巴细胞白血病的关键调节因子。Bcl-2家族蛋白受不同的蛋白-蛋白相互作用调控。利用模拟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种针对Bcl-2家族某些成员的化合物。然而，迄今为止，在开发选择性靶向Mcl-1功能的BH3模拟物方面所做的努力很少，尽管已经确定了对此类化合物的需求。在这里，我们提出了一项努力，以做到这一点，使用药物化学方法，将由两项新技术的支持。我们的起始化合物EU-517是在哈佛医学院的BH3肽结合Bcl-xL抑制剂的小分子筛选中发现的。最近，对Mcl-1具有优先活性的衍生物被制造出来。这些将作为开发抗mcl -1先导化合物的起点。来自哈佛医学院Gerhard Wagner实验室的创新灵活对接模型将用于指导导联优化。一种新的基于细胞的检测方法可以复制Mcl-1“癌基因成瘾”状态，并将用于选择合适的抗Mcl-1活性。这项工作将得到这两项技术的发明者、学术顾问格哈德·瓦格纳和安东尼·勒泰的支持。药物化学计划已经到位，将由位于马萨诸塞州梅德福的MedChem Partners Inc.实施。公共卫生相关性：Eutropics已经组建了一个强大的科学团队来开发称为BH3模拟物[4]的抗癌疗法。最近，我们发现了一种BH3模拟化合物的抗肿瘤活性，该化合物现已获得哈佛医学院的许可。在体外和细胞实验中，该化合物及其衍生物具有抑制髓样因子-1（Mcl-1）蛋白的活性。Mcl-1已被证明是某些血癌的病因[9,10,11]，被认为是一种可行的药物靶点。在这里，我们建议利用两种新技术来支持药物化学的努力，以开发选择性Mcl-1抑制化合物。

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 B-cell lymphoma, multiple myeloma, and chronic lymphocytic leukemia. The Bcl-2 family proteins are 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 very little effort in developing BH3 mimetics that selectively target the Mcl-1 function, though there is an identified need for such compounds. Here we propose an effort to do this using a medicinal chemistry approach that will be bolstered by two novel technologies. Our starting compound, EU-517 was discovered at Harvard Medical School in a small molecule screen for inhibitors of BH3 peptide binding to Bcl-xL. More recently derivatives that have preferential activity against Mcl-1 were made. These will be used as the starting point for developing an anti-Mcl-1 lead compound. An innovative flexible docking model that comes from the Gerhard Wagner lab at Harvard Medical School will be used to guide lead optimization. A novel cell based assay that replicates the Mcl-1 "oncogene addicted" state is licensed from Dana Farber and will be used to select appropriate anti-Mcl-1 activity. This effort will receive support from academic consultants Gerhard Wagner and Anthony Letai, the inventors of the two technologies. The medicinal chemistry plan is in place and will be carried out by MedChem Partners Inc. in Medford MA. PUBLIC HEALTH RELEVANCE:Eutropics has assembled a strong science team to develop anti-cancer therapeutics called BH3 mimetics [4]. Recently we found anti- tumor activity of a BH3 mimetic compound that Eutropics has now licensed from Harvard Medical School. This compound and now its derivatives have activity in inhibiting the myeloid factor-1(Mcl-1) protein in in vitro and cell based assays. Mcl-1 has been shown to be causal in certain blood cancers [9,10,11] and is considered a viable drug target. Here we propose utilizing two novel technologies to bolster a medicinal chemistry effort to develop selective Mcl-1 inhibiting compounds.