McI-1 Inhibitors for the treatment of Breast Cancer

用于治疗乳腺癌的 MCI-1 抑制剂

• 批准号: 8593797
• 负责人: Rebecca Sara Cook
• 金额: $ 15.36万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-07 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8593797
• 关键词: Affinity; Antineoplastic Agents; Apoptotic; Binding; Biological Markers; Breast Cancer Cell; Breast Cancer Model; Breast Cancer Treatment; Cell Death Process; Cell Proliferation; Cell Survival; Cells; Clinic; Clinical Trials; Defect; Development; Drug Targeting; Gene Amplification; Genetic; Human; Instruction; Maintenance; Malignant Neoplasms; Mammary Neoplasms; Metabolism; Methods; Molecular Genetics; Mutation; Myeloid Cells; Normal tissue morphology; Patients; Pharmacologic Substance; Property; Proteins; Reporting; Resistance; Signal Transduction; Structure; Testing; Virulent; base; breast tumorigenesis; chemotherapy; design; in vivo; inhibitor/antagonist; leukemia; malignant breast neoplasm; neoplastic cell; novel; overexpression; pre-clinical; pro-apoptotic protein; restoration; small molecule; triple-negative invasive breast carcinoma; tumor; tumor initiation

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.

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