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

开发用于癌症治疗的Mcl-1小分子抑制剂

• 批准号: 7538205
• 负责人: MICHAEL H CARDONE
• 金额: $ 32.7万
• 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 2009-05-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7538205
• 关键词: ADME Study; Animals; Apoptosis; B-Cell Lymphomas; B-Cell Neoplasm; B-Lymphocytes; BH3 Domain; BH3 peptide; Binding; Biological Assay; Blood Cells; Cell Line; Cells; Chemicals; Chronic Lymphocytic Leukemia; Class; Clinical Trials; Computer Simulation; Confidential Information; Cytochrome P450; Data; Development; Disease regression; Docking; Drug Delivery Systems; Drug Formulations; Drug Kinetics; Engineering; Family; Hematopoietic Neoplasms; In Vitro; Inhibitory Concentration 50; Lead; Libraries; Licensing; Lymphoid; Lymphoid Cell; MCL1 protein; Malignant Neoplasms; Maximum Tolerated Dose; Measures; Metabolic; Methodology; Methods; Mitochondria; Modeling; Modification; Multiple Myeloma; Mus; Myelogenous; Myeloid Cells; Oncogenes; Permeability; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase; Probability; Process; Production; Protein Binding; Protein Family; Proteins; Public Health; Publishing; Qualifying; Research; Science; Screening procedure; Small Business Funding Mechanisms; Small Business Innovation Research Grant; Solubility; Staging; Structure; Technology; Test Result; Testing; Toxic effect; Toxicology; analog; anti-cancer therapeutic; base; human MCL1 protein; improved; in vivo; inhibitor/antagonist; innovation; killings; leukemia; medical schools; member; mimetics; mouse model; neoplastic cell; new technology; novel; oncology; programs; protein protein interaction; scaffold; small molecule; success; tumor; tumor xenograft

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.

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)是该蛋白家族的一员，是B细胞淋巴瘤、多发性骨髓瘤和慢性淋巴细胞白血病等淋巴系肿瘤的关键调节因子。Bcl2家族蛋白受不同的蛋白质间相互作用的调节。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，开发选择性靶向Mcl-1功能的BH3模拟物的努力很少，尽管已经确定需要这样的化合物。在这里，我们建议使用一种药物化学方法来实现这一点，该方法将得到两项新技术的支持。我们的起始化合物EU-517是在哈佛医学院发现的，它是在一个小分子筛选中发现的，目的是寻找BH3多肽与Bcl-XL结合的抑制剂。最近，对Mcl-1具有优先活性的衍生物被制造出来。这些将被用作开发抗Mcl-1先导化合物的起点。来自哈佛医学院格哈德·瓦格纳实验室的一种创新的灵活对接模型将用于指导引线优化。一种复制Mcl-1“癌基因成瘾”状态的新的基于细胞的分析方法获得了Dana Farber的许可，并将用于选择适当的抗Mcl-1活性。这一努力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，并将由位于马萨诸塞州梅德福德的MedChem Partners Inc.执行。与公共卫生相关：Eutroics已经组建了一个强大的科学团队来开发名为BH3模拟疗法的抗癌疗法[4]。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检测中具有抑制髓系因子-1(Mcl-1)蛋白的活性。MCL-1已被证明与某些血癌有因果关系[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来支持药物化学努力，以开发选择性的Mcl-1抑制化合物。

项目成果

Hydroxyquinoline-derived compounds and analoguing of selective Mcl-1 inhibitors using a functional biomarker.

• DOI: 10.1016/j.bmc.2013.08.017
• 发表时间: 2013-11-01
• 期刊: Bioorganic & medicinal chemistry
• 影响因子: 3.5
• 作者: Richard DJ;Lena R;Bannister T;Blake N;Pierceall WE;Carlson NE;Keller CE;Koenig M;He Y;Minond D;Mishra J;Cameron M;Spicer T;Hodder P;Cardone MH
• 通讯作者: Cardone MH