pBACH1 binding site on BRCT(BRCA1): A novel approach to cancer therapeutics

BRCT (BRCA1) 上的 pBACH1 结合位点：癌症治疗的新方法

基本信息

批准号：
7924608
负责人：
Amarnath Natarajan
金额：
$ 27.9万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-08 至 2013-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7924608
关键词：
Adjuvant Adriamycin PFS Alberta province Amino Acids Antineoplastic Agents Apoptosis BRCA1 gene BRCT Domain Binding Binding Sites Biochemical Biological Assay Bleomycin Breast Breast Cancer Cell Canada Cancer Biology Cancer Etiology Cancer Patient Cell physiology Cells Chlorambucil Cisplatin Clinic Clinical Research Collaborations Complex Computer software Consultations Control Groups Coupled Crystallization Cyclophosphamide DNA Damage DNA Repair Data Diversity Library Docking Dose Drug Combinations Etoposide Female Fluorescence Polarization Fluorouracil Foundations Frequencies Genetic Transcription Growth Inbred BALB C Mice Inhibition of Apoptosis Kinetics Lead Letters Ligands Luciferases Malignant Neoplasms Malignant neoplasm of ovary Measures Melphalan Microtubules Mitomycins Molecular Mus Mutation Nude Mice Ovarian Tissue Paclitaxel Patients Pharmaceutical Chemistry Pharmaceutical Preparations Phosphopeptides Proteins Radiation Regulation Reporter Research Resistance Roentgen Rays Route Screening Result Screening procedure Simulate Structure Structure-Activity Relationship System Testing Therapeutic Therapeutic Agents Universities Vinblastine Vincristine Woman X-Ray Crystallography Xenograft procedure abdominal fat analog anticancer activity antitumor agent base cancer cell cancer therapy chemotherapeutic agent chemotherapy clinically relevant design drug efficacy helicase high throughput screening inhibitor/antagonist innovation insight irinotecan mouse model mutant novel novel strategies preclinical study programs protein protein interaction research study response small molecule structural biology therapeutic target tool tumor tumor progression

项目摘要

DESCRIPTION (provided by applicant): BReast CAncer gene 1 (BRCA1) encodes for an 1863 amino acid protein. The C-terminus domains of BRCA1 (BRCT) interact with a variety of other proteins to facilitate cellular functions such as checkpoint regulation, DNA damage response and DNA repair. Mutations found in the BRCT domains of BRCA1, result in the formation of tumors in the breast and ovarian tissues. These mutations genetically predispose women to breast and ovarian cancers. However, retrospective clinical studies show that patients with mutations in the BRCT domains respond better to chemotherapy. M1775R is a cancer causing mutation found in the BRCT domains of BRCA1. The molecular basis for the cancer caused by the M1775R mutant protein has been attributed to the loss of BRCTM1775R binding to phosphorylated proteins, such as the carboxy helicase BACH1 (pBACH1). Biochemical and preclinical studies have shown that the BRCT-pBACH1 interaction is essential for check point regulation and DNA repair and cells carrying BRCT mutants are sensitive to DNA damaging chemotherapeutic agents. Taken together, these studies indicate that cancers with the BRCT mutations respond better to therapy due to the loss of BRCT DNA repair function. Using a combination of cell-free and cell-based assay we identified a small molecule inhibitor (BI-94) of the BRCT-pBACH1 interaction. We also show that BI-94 sensitizes breast cancer cells to growth inhibition and apoptosis induced by Etoposide and Bleomycin. In this application, we propose to continue these studies by 1) exploring if the resistance induced by the BRCT-pBACH1 interaction towards Bleomycin / Etoposide treatment extends to other breast and ovarian cancer therapeutics in specific aim 1 and 2) advance BI-94 / or a close analog as an anti-cancer agent through specific aims 2-4.PROJECT NARRATIVE In this application we propose to develop small molecule inhibitors of protein-protein interaction. The successful completion of this project will 1) provide valuable tools to understand the genesis and progression of cancers due to BRCA1 mutation and 2) provide lead compounds that can be developed as chemotherapeutic agents to treat sporadic breast and ovarian cancer patients.

描述（由申请人提供）：乳腺癌基因1（BRCA1）编码1863个氨基酸的蛋白质。 BRCA1 (BRCT) 的 C 末端结构域与多种其他蛋白质相互作用，以促进细胞功能，例如检查点调节、DNA 损伤反应和 DNA 修复。 BRCA1 的 BRCT 结构域中发现的突变会导致乳腺和卵巢组织中肿瘤的形成。这些突变在基因上使女性容易患乳腺癌和卵巢癌。然而，回顾性临床研究表明，BRCT 结构域发生突变的患者对化疗的反应更好。 M1775R 是在 BRCA1 的 BRCT 结构域中发现的一种致癌突变。 M1775R 突变蛋白引起癌症的分子基础归因于 BRCTM1775R 与磷酸化蛋白（例如羧基解旋酶 BACH1 (pBACH1)）结合的丧失。生化和临床前研究表明，BRCT-pBACH1 相互作用对于检查点调节和 DNA 修复至关重要，并且携带 BRCT 突变体的细胞对 DNA 损伤性化疗药物敏感。总而言之，这些研究表明，由于 BRCT DNA 修复功能的丧失，带有 BRCT 突变的癌症对治疗的反应更好。通过结合无细胞和基于细胞的测定，我们鉴定了 BRCT-pBACH1 相互作用的小分子抑制剂 (BI-94)。我们还表明，BI-94 使乳腺癌细胞对依托泊苷和博来霉素诱导的生长抑制和细胞凋亡敏感。在本申请中，我们建议通过以下方式继续这些研究：1) 探索 BRCT-pBACH1 相互作用诱导的对博来霉素/依托泊苷治疗的耐药性是否扩展到具体目标 1 和 2 中的其他乳腺癌和卵巢癌治疗）推进 BI-94/或通过特定目标作为抗癌剂的类似物 2-4.项目叙述在本申请中，我们建议开发蛋白质-蛋白质相互作用的小分子抑制剂。该项目的成功完成将1）提供有价值的工具来了解BRCA1突变引起的癌症的发生和进展，2）提供可开发为化疗药物来治疗散发性乳腺癌和卵巢癌患者的先导化合物。