Screening for inhibitors of orphan nuclear receptor DAX-1

孤儿核受体 DAX-1 抑制剂的筛选

• 批准号: 8074951
• 负责人: Enzo LALLI
• 金额: $ 2.62万
• 依托单位: CNRS--DELEGATION COTE D'AZUR
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8074951
• 关键词: Adolescent; Binding Sites; Biological Assay; C-terminal; Child; Development; Enzyme Gene; Genes; Growth; Health Sciences; Luciferases; Malignant Neoplasms; Measures; Mission; NP protein; NR0B1 gene; Nuclear Orphan Receptor; Pharmaceutical Preparations; Property; Reporter; Research; Role; Schedule; Screening procedure; Soft Tissue Neoplasms; Testing; Therapeutic; Toxic effect; Transcription Repressor/Corepressor; Transfection; Tumor Cell Line; United States; United States National Institutes of Health; cancer therapy; improved; inhibitor/antagonist; interest; programs; public health relevance; small molecule; stem cell biology; tool; transcription factor

DESCRIPTION (provided by applicant): The aim of this study will be to identify small-molecule inhibitors of orphan nuclear receptor DAX-1 (NR0B1) through a HTS screening program. Inhibition of DAX-1 activity has a potential interest as a therapeutic tool in the domains of stem cell biology and cancer. Inhibitor screening will be performed by a simple transfection assay using as readout the relief of the transcriptional repressor activity of a Gal4 - DAX-1 C-terminal domain fusion on a luciferase reporter harboring Gal4 binding sites. Countersreen assays will subsequently involve the study of the activity of the hit molecules identified during the primary HTS campaign on DAX-1 transcriptional properties measured on a battery of DAX-1 responsive reporters, i.e. steroidogenic enzyme genes. Finally, tertiary assays will be aimed at developing compounds with improved DAX-1 inhibitor potency, assess their selectivity of action against other transcription factors and measure their toxicity. Furthermore, the efficacy of the inhibitors will be tested on DAX-1 - dependent growth of tumor cell lines. PUBLIC HEALTH RELEVANCE: Development of new drugs displaying increased selectivity and less toxicity is of utmost importance for modern anticancer therapy. Our project has the aim to search for new inhibitors for the orphan nuclear receptor DAX-1, which has a pivotal role in the growth of a specific type of soft tissue tumor of children and adolescents.

描述（由申请方提供）：本研究的目的是通过HTS筛选程序鉴定孤儿核受体DAX-1（NR 0 B1）的小分子抑制剂。DAX-1活性的抑制具有作为干细胞生物学和癌症领域中的治疗工具的潜在兴趣。抑制剂筛选将通过简单的转染测定进行，使用Gal 4- DAX-1 C-末端结构域融合物在含有Gal 4结合位点的荧光素酶报告物上的转录阻遏物活性的减轻作为读数。随后，Countersreen测定将涉及在主要HTS活动期间鉴定的命中分子对DAX-1转录特性的活性的研究，所述DAX-1转录特性是在DAX-1响应报告基因组上测量的，即类固醇生成酶基因。最后，三级试验将旨在开发具有改善的DAX-1抑制剂效力的化合物，评估其对其他转录因子的作用选择性并测量其毒性。此外，将在肿瘤细胞系的DAX-1依赖性生长上测试抑制剂的功效。 公共卫生相关性：开发具有更高选择性和更低毒性的新药对现代抗癌治疗至关重要。我们的项目旨在寻找孤儿核受体DAX-1的新抑制剂，DAX-1在儿童和青少年特定类型软组织肿瘤的生长中具有关键作用。