McI-1 Inhibitors for the treatment of Breast Cancer

用于治疗乳腺癌的 MCI-1 抑制剂

基本信息

批准号：
8764759
负责人：
Rebecca Sara Cook
金额：
$ 31.8万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-01 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8764759
关键词：
2-cyclopentyl-5-(5-isoquinolylsulfonyl)-6-nitro-1H-benzo(D)imidazole Affinity Antineoplastic Agents Apoptotic BCL2 gene Binding Biological Markers Breast Cancer Cell Breast Cancer Model Breast Cancer Treatment Cancer cell line Cell Death Process Cell Proliferation Cell Survival Cells Clinic Clinical Trials Defect Development Doctor of Philosophy Drug Kinetics Drug Targeting Family Future Gene Amplification Gene Dosage Gene Expression Genetic Genetically Engineered Mouse Genomics Goals Human Immune system Instruction Lead Maintenance Malignant Neoplasms Mammary Neoplasms Mediating Metabolism Methodology Methods Microtubules Molecular Genetics Molecular Profiling Mutation Myeloid Cells Normal tissue morphology Patients Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacologic Substance Property Protein Overexpression Proteins RNA Interference Relative (related person)Reporting Resistance Signal Transduction Structure Taxane Compound Testing Therapeutic Virulent Xenograft procedure analog base breast tumorigenesis chemotherapeutic agent chemotherapy design drug metabolism in vivo inhibitor/antagonist iterative design leukemia loss of function malignant breast neoplasm molecular marker mouse model neoplastic cell novel overexpression pre-clinical pro-apoptotic protein protein protein interaction response restoration small molecule taxane triple-negative invasive breast carcinoma tumor tumor initiation tumor microenvironment

项目摘要

instnjctions): Amplification of the gene encoding the anti-apoptotic protein myeloid cell leukemia-1 (Mcl-1) is a common genetic aberration in breast cancer. Mcl-1 overexpression in human cancers is associated with high tumor grade, resistance to chemotherapy and poor patient survival. Preclinical evidence suggests that Mcl-1 is a promising target for the treatment of breast cancers including the highly aggressive triple negative breast cancer (TNBC) subtype. Although attempts to target Mcl-1 have been reported, compounds specifically targeting Mcl-1 have not entered the clinic. Using a combination of fragment-based methods and structure- based design, we have discovered novel small molecules that bind to Mcl-1 with high affinity (KD - 35 nM) for the BH3-binding pocket, the motif used by Mcl-1 to bind to and sequester pro-apoptotic proteins. Therefore, we hypothesize that targeted inhibition of Mcl-1 will result in restoration of apoptotic signaling and increased sensitivity to chemotherapy in Mcl-1-dependent breast tumors. To test this hypothesis, we propose the following specific aims: Aim 1. Discover potent (sub-nanomolar) and specific Mcl-1 inhibitors using fragment-based methods and structure-based design Aim 2. Optimize potent Mcl-1 inhibitors for their cell-based activities, pharmaceutical properties and In vivo efficacy in breast cancer models Aim 3. Identify genetic and molecular biomarkers of sensitivity to Mcl-1 inhibition, alone or in combination with other anticancer agents with a focus in TNBC RELEVANCE (See instructions): Preclinical evidence suggests Mcl-1 is a common genetic alteration in breast cancer, including the virulent TNBC subtype. Development of rational and novel targeted drugs against this subtype of breast cancer is a major unmet need. We propose herein a translational project aimed at developing a potent and specific Mcl-1 inhibitor that will be ready for clinical trials within 5 years.

Instnjctions）：编码抗凋亡蛋白髓样细胞白血病1（MCL-1）的基因的扩增是一种常见乳腺癌的遗传像差。人类癌症中的MCL-1过表达与高肿瘤有关等级，对化疗的抵抗力和患者生存不良。临床前证明MCL-1是有望治疗乳腺癌的目标癌症（TNBC）亚型。尽管已经报告了针对MCL-1的尝试，但专门的化合物靶向MCL-1尚未进入诊所。结合基于碎片的方法和结构 - 基于设计，我们发现了新型的小分子，这些分子与高亲和力（KD -35 nm）结合的新型小分子 BH3结合口袋是MCL-1用于结合并隔离促凋亡蛋白的基序。因此，我们假设靶向抑制MCL-1将导致凋亡信号的恢复并增加对MCL-1依赖性乳腺肿瘤的化学疗法的敏感性。为了检验这一假设，我们提出了遵循特定目的： AIM 1。使用基于片段的方法和基于结构的设计 AIM 2。优化有效的MCL-1抑制剂，用于基于细胞的活性，药物特性和体内乳腺癌模型的功效目标3。单独或与MCL-1抑制的敏感性确定遗传和分子生物标志物其他抗癌剂，重点是TNBC 相关性（请参阅说明）：临床前证据表明，MCL-1是乳腺癌中常见的遗传改变，包括有毒 TNBC亚型。针对这种乳腺癌亚型的理性和新型靶向药物的开发是一种主要的未满足需求。我们在此提出了一个旨在开发有效和特定的MCL-1的翻译项目抑制剂将在5年内准备好进行临床试验。