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家族蛋白由不同的蛋白质-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，在开发选择性靶向Mcl-1功能的BH 3模拟物方面的努力很少，尽管确定需要这样的化合物。在这里，我们提出了一种使用药物化学方法来实现这一目标的努力，该方法将得到两种新技术的支持。我们的起始化合物EU-517是在哈佛医学院的一项小分子筛选中发现的，用于抑制Bcl-xL结合的BH 3肽。最近制备了对Mcl-1具有优先活性的衍生物。这些将用作开发抗Mcl-1先导化合物的起点。来自哈佛医学院Gerhard瓦格纳实验室的一种创新的灵活对接模型将用于指导铅优化。Dana Farber授权了一种新的基于细胞的试验，该试验可复制Mcl-1“癌基因成瘾”状态，并将用于选择适当的抗Mcl-1活性。这一努力将得到两项技术的发明者、学术顾问格哈德瓦格纳和安东尼勒泰的支持。药物化学计划已制定，并将由MedChem Partners Inc.执行。在Medford MA。公共卫生相关性：Eutropics组建了一支强大的科学团队，开发称为BH 3模拟物的抗癌疗法[4]。最近，我们发现了一种BH 3模拟化合物的抗肿瘤活性，Eutropics现已从哈佛医学院获得许可。该化合物及其衍生物在体外和基于细胞的测定中具有抑制髓样因子-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]，并被认为是一个可行的药物靶点。在这里，我们建议利用两种新技术，以支持药物化学的努力，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.