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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：
8307000
负责人：
Amarnath Natarajan
金额：
$ 27.06万
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 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8307000
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 Mammary Gland Parenchyma 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 malignant breast neoplasm 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）：BReast CAncer基因1（BRCA 1）编码1863个氨基酸的蛋白质。BRCA 1（BRCT）的C-末端结构域与各种其他蛋白质相互作用，以促进细胞功能，如检查点调节，DNA损伤反应和DNA修复。在BRCA 1的BRCT结构域中发现的突变导致乳腺和卵巢组织中肿瘤的形成。这些突变在遗传上使妇女易患乳腺癌和卵巢癌。然而，回顾性临床研究表明，BRCT结构域突变的患者对化疗的反应更好。M1775 R是在BRCA 1的BRCT结构域中发现的致癌突变。由M1775 R突变蛋白引起的癌症的分子基础已被归因于BRCTM 1775 R与磷酸化蛋白（如羧基解旋酶BACH 1（pBACH 1））结合的丧失。生物化学和临床前研究表明，BRCT-pBACH 1相互作用对于检查点调节和DNA修复是必不可少的，并且携带BRCT突变体的细胞对DNA损伤化疗剂敏感。总之，这些研究表明，由于BRCT DNA修复功能的丧失，具有BRCT突变的癌症对治疗的反应更好。使用无细胞和基于细胞的测定的组合，我们鉴定了BRCT-pBACH 1相互作用的小分子抑制剂（BI-94）。我们还表明，BI-94敏感乳腺癌细胞的生长抑制和凋亡诱导的依托泊苷和博莱霉素。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-pBACH 1相互作用诱导的对博来霉素/依托泊苷治疗的耐药性是否延伸至特定目的1中的其他乳腺癌和卵巢癌治疗，2）通过特定目的2- 4.项目叙述在本申请中，我们提出开发蛋白质-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由于BRCA 1突变引起的癌症的发生和进展，2）提供可开发为治疗散发性乳腺癌和卵巢癌患者的化疗药物的先导化合物。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Face selective reduction of the exocyclic double bond in isatin derived spirocyclic lactones.

DOI：
10.1039/c2ob27008k
发表时间：
2013-01-14
期刊：
Organic & biomolecular chemistry
影响因子：
3.2
作者：
Rana S;Natarajan A
通讯作者：
Natarajan A

Perturbing pro-survival proteins using quinoxaline derivatives: a structure-activity relationship study.

DOI：
10.1016/j.bmc.2012.02.022
发表时间：
2012-04-01
期刊：
BIOORGANIC & MEDICINAL CHEMISTRY
影响因子：
3.5
作者：
Rajule, Rajkumar;Bryant, Vashti C.;Lopez, Hernando;Luo, Xu;Natarajan, Amarnath
通讯作者：
Natarajan, Amarnath

Inhibition of BRCT(BRCA1)-phosphoprotein interaction enhances the cytotoxic effect of olaparib in breast cancer cells: a proof of concept study for synthetic lethal therapeutic option.

DOI：
10.1007/s10549-012-2079-4
发表时间：
2012-07
期刊：
BREAST CANCER RESEARCH AND TREATMENT
影响因子：
3.8
作者：
Pessetto, Ziyan Yuan;Yan, Ying;Bessho, Tadayoshi;Natarajan, Amarnath
通讯作者：
Natarajan, Amarnath

Novel treatment for mantle cell lymphoma including therapy-resistant tumor by NF-κB and mTOR dual-targeting approach.

DOI：
10.1158/1535-7163.mct-13-0239
发表时间：
2013-10
期刊：
Molecular cancer therapeutics
影响因子：
5.7
作者：
Chaturvedi NK;Rajule RN;Shukla A;Radhakrishnan P;Todd GL;Natarajan A;Vose JM;Joshi SS
通讯作者：
Joshi SS

Computational and experimental studies of the interaction between phospho-peptides and the C-terminal domain of BRCA1.

DOI：
10.1007/s10822-011-9484-3
发表时间：
2011-11
期刊：
JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN
影响因子：
3.5
作者：
Anisimov, Victor M.;Ziemys, Arturas;Kizhake, Smitha;Yuan, Ziyan;Natarajan, Amarnath;Cavasotto, Claudio N.
通讯作者：
Cavasotto, Claudio N.