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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.

说明）：编码抗凋亡蛋白髓细胞白血病-1（Mcl-1）的基因扩增是一种常见的乳腺癌的遗传变异人类癌症中Mcl-1过表达与高肿瘤发生率相关分级、化疗抵抗和患者生存率差。临床前证据表明，Mcl-1是一种治疗乳腺癌的有希望的靶点，包括高度侵袭性的三阴性乳腺癌癌症（TNBC）亚型。尽管已经报道了靶向Mcl-1的尝试，但化合物特别是以Mcl-1为目标的人还没有进入诊所使用基于片段的方法和结构的组合- 基于设计，我们发现了新的小分子，其以高亲和力（KD - 35 nM）结合Mcl-1， BH 3结合口袋，Mcl-1用于结合和隔离促凋亡蛋白的基序。所以我们假设Mcl-1靶向抑制将导致细胞凋亡信号的恢复和增加 Mcl-1依赖性乳腺肿瘤对化疗的敏感性为了验证这一假设，我们提出了具体目标如下：目标1.使用基于片段的方法发现强效（亚纳摩尔）和特异性Mcl-1抑制剂，基于结构的设计目标二。优化有效的Mcl-1抑制剂的细胞活性、药物特性和体内活性在乳腺癌模型中的疗效目标3.鉴定对Mcl-1抑制敏感的遗传和分子生物标志物，单独或与关注TNBC的其他抗癌药物相关性（参见说明）：临床前证据表明，Mcl-1是乳腺癌中常见的遗传变异，包括恶性肿瘤。 TNBC亚型。开发针对这种亚型乳腺癌的合理和新型靶向药物是一个重要的研究方向。未满足的重大需求。我们在此提出了一个翻译项目，旨在开发一个有效的和具体的Mcl-1 该抑制剂将在5年内准备好进行临床试验。