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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.

指令）：编码抗凋亡蛋白骨髓细胞白血病-1 (Mcl-1) 的基因扩增是一种常见的乳腺癌的基因畸变。 Mcl-1在人类癌症中的过度表达与高肿瘤相关级、化疗耐药性和患者生存率低。临床前证据表明 Mcl-1 是一种治疗乳腺癌（包括高度侵袭性三阴性乳腺癌）的有希望的目标癌症（TNBC）亚型。尽管已经报道了针对 Mcl-1 的尝试，但具体化合物靶向Mcl-1的药物尚未进入临床。使用基于片段的方法和结构的组合基于设计，我们发现了能够以高亲和力 (KD - 35 nM) 结合 Mcl-1 的新型小分子 BH3 结合口袋，Mcl-1 使用该基序结合并隔离促凋亡蛋白。因此，我们假设靶向抑制 Mcl-1 将导致细胞凋亡信号恢复并增加 Mcl-1 依赖性乳腺肿瘤对化疗的敏感性。为了检验这个假设，我们提出以下具体目标：目标 1. 使用基于片段的方法和方法发现有效的（亚纳摩尔）和特异性的 Mcl-1 抑制剂基于结构的设计目标 2. 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功效目标 3. 单独或与 Mcl-1 抑制联合识别对 Mcl-1 抑制敏感的遗传和分子生物标志物其他专注于 TNBC 的抗癌药物相关性（参见说明）：临床前证据表明 Mcl-1 是乳腺癌中常见的基因改变，包括致命的乳腺癌 TNBC 亚型。开发针对这种乳腺癌亚型的合理且新颖的靶向药物是一个迫切需要解决的问题。主要未满足的需求。我们在此提出一个旨在开发有效且特异的 Mcl-1 的转化项目抑制剂将在5年内准备好进行临床试验。