Small Molecule Inhibitors of the MCL-1 Survival Pathway for Cancer Therapy

MCL-1 生存途径的小分子抑制剂用于癌症治疗

• 批准号: 9069751
• 负责人: Paul Jeng
• 金额: $ 4.36万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9069751
• 关键词: Activities of Daily Living; Apoptosis; Apoptotic; BCL-2 Protein; BCL1 Oncogene; BCL2 gene; BCL2L11 gene; Binding; Bioavailable; Biological; Biological Assay; Cell Death; Cell Line; Cells; Cessation of life; Chemicals; Complex; Development; Embryo; Fibroblasts; Genes; Goals; Homologous Gene; Human; Internal Ribosome Entry Site; Lead; Length; Libraries; Malignant Neoplasms; Mediating; Mitochondria; Molecular Mechanisms of Action; Molecular Target; Mus; Pathologic; Pathway interactions; Protein Family; Protein Overexpression; Proteins; Protocols documentation; Regulation; Reporting; Research Proposals; Resistance; Specificity; Structure; Structure-Activity Relationship; Therapeutic; Wild Type Mouse; analog; base; cancer cell; cancer therapy; cancer type; chemotherapy; design; high throughput screening; inhibitor/antagonist; member; mimetics; novel; novel strategies; overexpression; protein degradation; public health relevance; response; small molecule; small molecule inhibitor; tumor; tumor initiation

DESCRIPTION (provided by applicant): MCL-1 is a member of the B-Cell Lymphoma 2 (BCL-2) protein family that regulates cell death via mitochondrion-initiated apoptosis. Under normal conditions, antiapoptotic MCL-1 and its functional homologs BCL-2 and BCL-XL serve as prosurvival regulators that preserve mitochondrial integrity and protect against unwanted cell death. However, pathologic overexpression of these proteins subverts the natural death response and contributes to tumor initiation, progression, and resistance to chemotherapeutics. Prosurvival BCL-2 proteins have consequently become attractive targets for antitumor therapy. The most specific inhibitors of anti-apoptotic BCL-2 family proteins, ABT-737 and its orally bioavailable analog ABT-263, bind the hydrophobic binding groove of BCL-2 and BCL-XL to liberate trapped proapoptotic BCL-2 members. However, ABT-737/263 are unable to target MCL-1 due to its unique structure. Cancer cells with MCL-1 amplifications have been shown to be addicted to MCL-1 for survival, and MCL-1 is among the top 10 most frequently amplified genes in all human cancer types. Therefore, selective small molecule targeting of MCL-1 remains a promising unfulfilled goal for cancer therapy. In cancer cells, BIM is the most relevant activator BH3 that binds most tightly with MCL-1, yet current small molecule MCL-1 inhibitors have been reported to be able to displace tBID but not BIM from MCL-1. We have developed a cell-based high throughput screening strategy to identify small molecule inhibitors of the MCL-1-dependent survival pathway that focuses specifically on the MCL-1/BIM complex. This novel strategy enables the identification of small molecules that either directly release BIM by disrupting the binding of BIM to the hydrophobic binding pocket of MCL-1 or indirectly through targeting MCL-1 for degradation. We have conducted pilot screens using 1,900 compounds of the NCI Diversity Set and first 10,000 compounds of the ChemBridge DiverSet (50,080 compounds) and identified 17 lead compounds that triggered apoptosis in cancer cells that are addicted to MCL-1 for survival. Here we propose to use a top-down approach to (1) identify inhibitors of MCL-1 at any level of its regulation, elucidate their molecular mechanisms of action, and examine their functional capacities to sensitize cancer cell apoptosis; (2) screen the remaining 40,080 compounds of the ChemBridge DiverSet; (3) study the structure-activity relationship of MCL-1 lead compound inhibitors. We hypothesize that our screen will identify compounds that directly inhibit the hydrophobic binding groove of MCL-1, target MCL-1 for accelerated degradation, or induce proapoptotic BCL-2 proteins.

描述（由申请人提供）：MCL-1是B细胞淋巴瘤2（BCL-2）蛋白家族的成员，通过EGFR启动的细胞凋亡调节细胞死亡。在正常条件下，抗凋亡MCL-1及其功能同源物BCL-2和BCL-XL作为促生存调节剂，保护线粒体完整性并防止不必要的细胞死亡。然而，这些蛋白质的病理性过表达破坏了自然死亡反应，并有助于肿瘤的发生、进展和对化疗药物的耐药性。因此，促生存BCL-2蛋白成为抗肿瘤治疗的有吸引力的靶标。抗凋亡BCL-2家族蛋白的最特异性抑制剂ABT-737及其口服生物可利用的类似物ABT-263结合BCL-2和BCL-XL的疏水结合沟以释放捕获的促凋亡BCL-2成员。然而，ABT-737/263由于其独特的结构而不能靶向MCL-1。具有MCL-1扩增的癌细胞已被证明依赖于MCL-1生存，并且MCL-1是所有人类癌症类型中前10个最频繁扩增的基因之一。因此，MCL-1的选择性小分子靶向仍然是癌症治疗的有希望的未实现的目标。在癌细胞中，BIM是与MCL-1结合最紧密的最相关的激活剂BH 3，但据报道，目前的小分子MCL-1抑制剂能够取代MCL-1的tBID，但不能取代BIM。我们已经开发了一种基于细胞的高通量筛选策略来鉴定MCL-1依赖性存活途径的小分子抑制剂，该策略特别关注MCL-1/BIM复合物。这种新的策略使得能够鉴定通过破坏BIM与MCL-1的疏水结合口袋的结合而直接释放BIM或通过靶向MCL-1进行降解而间接释放BIM的小分子。我们使用NCI Diversity Set的1，900种化合物和ChemBridge DiverSet的前10，000种化合物（50，080种化合物）进行了初步筛选，并确定了17种引发癌细胞凋亡的先导化合物，这些癌细胞依赖MCL-1生存。在这里，我们建议使用自上而下的方法来（1）识别MCL-1在其调节的任何水平上的抑制剂，阐明它们的分子作用机制， （2）筛选ChemBridge DiverSet剩余的40，080个化合物;（3）研究MCL-1先导化合物抑制剂的构效关系。我们假设我们的筛选将鉴定直接抑制MCL-1的疏水结合沟、靶向MCL-1加速降解或诱导促凋亡BCL-2蛋白的化合物。