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Structure-based In silico Screen for Small Molecule Inhibitors of Ets-1 Activity

基于结构的 Ets-1 活性小分子抑制剂的计算机筛选

基本信息

批准号：
7499088
负责人：
ALAN C RIGBY
金额：
$ 16.66万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-21 至 2010-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7499088
关键词：
Affect Affinity Autoimmune Diseases Biological Assay Biological Process Biology Boxing CCAAT-Enhancer-Binding Proteins CCL2 gene Cells Chemicals Class Complex Computer Simulation DNA DNA Sequence DNA-Protein Interaction Data Development Differentiation and Growth Disease Docking Electrophoretic Mobility Shift Assay Elements Evaluation Event Family member Functional disorder Gene Expression Gene Expression Regulation Genes Genetic Transcription Goals Histone Deacetylase In Vitro Inflammation Inflammatory Interleukin-1 Investigation Joints Label Laboratories Lead Libraries Malignant Neoplasms Mediating Metalloproteases Methyltransferase Mitolactol Molecular NF-kappa B NMR Spectroscopy Necrosis Nitric Oxide Numbers Nylons Pathologic Processes Pathway interactions Patients Process Prostaglandins Proteins Proteomics Publications Recombinants Research Personnel Rheumatoid Arthritis Role Science Screening procedure Signal Pathway Specificity Structure Synovial Membrane Therapeutic Therapeutic Agents Therapeutic Intervention Thinking Tissues Transactivation Transcriptional Activation Transcriptional Regulation Up-Regulation Validation Zinc Fingers arthritis therapy arthropathies base c-ets1 transcription factor chemokine chromatin immunoprecipitation concept cross reactivity cytokine expression cloning in vivo inhibitor/antagonist innovation man novel novel strategies novel therapeutics promoter repository scaffold skills small molecule therapeutic protein therapeutic target transcription factor tumor virtual

项目摘要

DESCRIPTION (provided by applicant): Inflammatory processes contribute to the pathological events that lead to tissue destruction in autoimmune diseases including rheumatoid arthritis (RA). For patients suffering with RA the development of therapeutic agents that are capable of blocking TNF1 and IL-1 have been important therapeutic milestones, however a significant number of patients fail to respond to these therapies possibly due to their inherent inability to inhibit other pathways requisite in this complex disease. Several laboratories have suggested that in order to further understand the pathophysiologies of RA new therapeutic targets need to be identified, targeted and validated. One potential class of targets is the cytokine-induced transcription factors; NF-k B, AP-1, C/EBP, and ETS-1 all of which have been detected in RA synovium. Several recent publications support the importance of targeting transcription factors (TFs), which would provide a mechanism of re-regulating gene expression pathways including the cytokine pathway through a controlled, rheostat "switch" rather than a binary on/off mechanism. In addition, a wealth of information and a better understanding of transcriptional biology and gene regulation supports that TFs themselves are potential targets for therapeutic intervention. The proposed project is highly innovative, partnering our translational discovery-based science with in vitro and in vivo validation of this novel target space, the TF-DNA interface for use in the development of first in man type RA therapy. This collaborative and truly synergistic application involving investigators with complementary skills partners the strengths of in silico structure-based small molecule discovery with NMR spectroscopy based target validation and in vitro characterization/evaluation in support of our approach for identifying and developing novel small molecules that specifically target and inhibit the interaction interface between Ets-1 and its sequence specific DNA promoter element. These investigators have unique strengths and expertise, which when partnered provides a significant opportunity for creative, "out of the box" thought and execution as demonstrated by the significant preliminary data in support of this application. Small molecules with demonstrable activity such as those identified represent an attractive opportunity for TF-dependent transcriptional regulation, providing an innovative strategy for the "hit-through-lead" development of therapeutic agents that selectively inhibit ETS TF activity at the TF-DNA level. This application is focused on selectively targeting this TF-DNA interface, which represents a novel approach for TF-dependent transcriptional regulation of Ets-1 and provides a unique opportunity for the development of therapeutic agents selectively targeting this transcription factor. Small molecule inhibition of the TF-DNA interaction interface provides a promising paradigm shift in transcriptional therapy for RA through pathway specific transcriptional regulation as has been attempted for nuclear factor kappa B (NF-kB).Through a wealth of information and a better understanding of transcriptional biology and gene regulation, TFs including NF-kB, HIF112 and others have emerged as novel targets for therapeutic intervention. The proposed project is highly innovative, partnering our translational discovery-based science with in vitro and in vivo validation of novel target space; the TF-DNA interface for use in the identification and subsequent development of novel therapies for RA. TFs are established regulators of gene expression and as such are requisite for a variety of biological processes, including growth, differentiation and development as well as pathological processes such as cancer and/or inflammation. Sequence-specific TF-DNA interactions are spatially and temporally regulated, resulting in refined specificity and selectivity at the protein-DNA interface. The ability to selectively target and inhibit the interaction interface of the TF-DNA complex represents a novel, highly specific strategy for reprogramming specific gene pathways that are deregulated in RA and cancer. Unlike other approaches including; polyamides, artificial transcription factors, zinc finger protein therapeutics we have proposed to partner in silico, virtual screening or high throughput docking (HTD) to screen large publicly accessible chemical repositories for small molecules that selectively target and thus inhibit this well-defined molecular interface. Importantly, in silico HTD is ideally suited for the exploration of novel target space such as the Ets-1 TF-DNA interaction interface. Our central hypothesis is that small molecules that target and disrupt this interface would be capable of regulating aberrant gene transcription and would thus offer a novel paradigm of therapy for RA. Those small molecule scaffolds that demonstrate significant in vivo activity would provide a transcriptional therapy platform for RA. This approach, if successful, represents an innovative and very unique opportunity to develop a "first in man" therapeutic approach that will selectively target and disrupt downstream TF-mediated gene expression by targeting the selectivity/specificity interface of the TF.

描述（由申请人提供）：炎症过程导致病理事件，导致包括类风湿性关节炎（RA）在内的自身免疫性疾病中的组织破坏。对于患有 RA 的患者来说，能够阻断 TNF1 和 IL-1 的治疗药物的开发一直是重要的治疗里程碑，然而，大量患者未能对这些疗法做出反应，可能是因为它们固有地无法抑制这种复杂疾病所需的其他途径。一些实验室建议，为了进一步了解 RA 的病理生理学，需要确定、靶向和验证新的治疗靶点。一类潜在的靶标是细胞因子诱导的转录因子； NF-k B、AP-1、C/EBP 和 ETS-1 均已在 RA 滑膜中检测到。最近的几篇出版物支持靶向转录因子（TF）的重要性，这将提供一种通过受控变阻器“开关”而不是二元开/关机制重新调节基因表达途径（包括细胞因子途径）的机制。此外，丰富的信息以及对转录生物学和基因调控的更好理解支持转录因子本身是治疗干预的潜在目标。拟议的项目具有高度创新性，将我们基于转化发现的科学与这一新颖靶点空间（TF-DNA 接口）的体外和体内验证相结合，用于开发首个人类型 RA 疗法。这种协作和真正协同的应用涉及具有互补技能的研究人员，结合了基于计算机结构的小分子发现与基于核磁共振波谱的目标验证和体外表征/评估的优势，支持我们识别和开发特异性靶向和抑制 Ets-1 及其序列特异性 DNA 启动子元件之间相互作用界面的新型小分子的方法。这些研究人员拥有独特的优势和专业知识，当合作时，这些优势和专业知识为创造性、“开箱即用”的思维和执行提供了重要的机会，正如支持该应用的重要初步数据所证明的那样。具有明显活性的小分子（例如那些已鉴定的小分子）代表了 TF 依赖性转录调控的一个有吸引力的机会，为开发在 TF-DNA 水平上选择性抑制 ETS TF 活性的治疗剂的“直通先导”开发提供了创新策略。该应用的重点是选择性靶向该 TF-DNA 界面，这代表了一种 TF 依赖性转录调控 Ets-1 的新方法，并为开发选择性靶向该转录因子的治疗药物提供了独特的机会。 TF-DNA 相互作用界面的小分子抑制为 RA 的转录治疗提供了一个有希望的范式转变，通过途径特异性转录调节，就像核因子 kappa B (NF-kB) 的尝试一样。通过大量信息和对转录生物学和基因调控的更好理解，包括 NF-kB、HIF112 等在内的 TF 已成为治疗干预的新靶点。拟议的项目具有高度创新性，将我们基于转化发现的科学与新目标空间的体外和体内验证相结合； TF-DNA 接口用于 RA 新疗法的识别和后续开发。转录因子是基因表达的既定调节因子，因此是多种生物过程所必需的，包括生长、分化和发育以及癌症和/或炎症等病理过程。序列特异性 TF-DNA 相互作用在空间和时间上受到调节，从而在蛋白质-DNA 界面上产生精细的特异性和选择性。选择性靶向和抑制 TF-DNA 复合物相互作用界面的能力代表了一种新颖的、高度特异性的策略，用于重新编程在 RA 和癌症中失调的特定基因途径。与其他方法不同的是，包括：聚酰胺、人工转录因子、锌指蛋白疗法，我们建议在计算机模拟、虚拟筛选或高通量对接（HTD）方面进行合作，以筛选大型公共化学存储库中的小分子，这些小分子选择性地靶向并从而抑制这种明确的分子界面。重要的是，计算机 HTD 非常适合探索新颖的目标空间，例如 Ets-1 TF-DNA 相互作用界面。我们的中心假设是，靶向并破坏该界面的小分子将能够调节异常基因转录，从而为 RA 提供一种新的治疗范例。那些表现出显着体内活性的小分子支架将为RA提供转录治疗平台。这种方法如果成功的话，代表着一个创新且非常独特的机会来开发“人类首个”治疗方法，该方法将通过靶向 TF 的选择性/特异性界面来选择性地靶向和破坏下游 TF 介导的基因表达。