权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Therapeutic targeting of MYC interactions with an essential cofactor

MYC 与重要辅因子相互作用的治疗靶向

基本信息

批准号：
10512309
负责人：
MICHAEL David COLE
金额：
$ 23万
依托单位：
DARTMOUTH COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10512309
关键词：
Address Amino Acid Motifs Binding Biological Biological Assay Biomedical Research Breast Cancer Cell Cancer Cell Growth Cause of Death Cell Proliferation Cells Cessation of life Chimeric Proteins Chromatin Collaborations Complex DNA Development Down-Regulation Evolution Gene Amplification Genes Genetic Transcription Goals Growth Helix-Turn-Helix Motifs Histone Acetylation Human Institutes Lead Leucine Zippers Luciferases MYC Family Protein Malignant Neoplasms Mass Spectrum Analysis Measurement Molecular Multienzyme Complexes Mutation Nuclear Nuclear Protein Oncogenic Pharmaceutical Preparations Protein Inhibition Proteins Series Signal Pathway Specificity TRRAP gene Therapeutic Transactivation anti-cancer therapeutic anticancer activity base cancer cell cancer therapy cell growth cofactor experimental study histone modification in vivo inhibitor metaplastic cell transformation nanomolar novel oncogene addiction overexpression preclinical development protein complex protein function recruit response small molecule inhibitor targeted treatment theories therapeutic target transcriptome sequencing triple-negative invasive breast carcinoma

项目摘要

MYC is the most frequently amplified gene in human cancer and is overexpressed as a consequence of mutations in diverse oncogenic signaling pathways in 70% of cancers. Given the ubiquity of MYC as a driver of cancer, there is a critical unmet need to develop specific drugs that inhibit MYC function as anti-cancer therapeutics. TRansactivation/tRansformation- domain Associated Protein (TRRAP) is an essential nuclear cofactor for MYC, and small molecule inhibitors of the MYC:TRRAP interaction are predicted to have potent anti-cancer activity. We developed a luciferase-based assay to identify small molecule inhibitors of MYC:TRRAP and initiated a collaboration with the Novartis Institute for Biomedical Research to search their non-proprietary 50,000 drug-like compound set. We identified 33 diverse compounds that show inhibitory activity for MYC:TRRAP in the nanomolar to micromolar concentration range using our luciferase assay. We propose to use cellular and molecular assays to determine which of these compounds inhibit native MYC:TRRAP complexes and ascertain their specificity regarding other MYC and/or TRRAP interacting proteins. Promising compounds will also be assayed for growth inhibitory activity in triple negative breast cancer cells, which have high levels of MYC and determine if growth inhibition can be attributed to loss of MYC function. A long-term goal is the preclinical development of our top lead compounds for in vivo experimentation.

MYC是人类癌症中最常扩增的基因，在70%的癌症中，不同致癌信号通路的突变是其结果。给定由于MYC作为癌症驱动因素的普遍存在，因此开发特异性MYC的关键需求尚未得到满足。抑制MYC功能的药物作为抗癌治疗剂。转录激活/转录- 结构域相关蛋白（TRRAP）是MYC的一种重要核辅因子， MYC：TRRAP相互作用的分子抑制剂被预测具有有效的抗癌活性，活动我们开发了一种基于谷胱甘肽转移酶的检测方法来鉴定小分子抑制剂， MYC：TRRAP，并发起了与诺华生物医学研究所的合作，搜索他们非专利的5万种类似药物的化合物我们发现了33种不同的显示出纳摩尔至微摩尔MYC：TRRAP抑制活性的化合物使用我们的荧光素酶测定法测定浓度范围。我们建议使用细胞和分子测定这些化合物中的哪一种抑制天然MYC：TRRAP复合物，确定它们对其他MYC和/或TRRAP相互作用蛋白的特异性。有前途还将测定化合物在三阴性乳腺癌中的生长抑制活性细胞，其具有高水平的MYC，并确定生长抑制是否可归因于损失 MYC功能。长期目标是临床前开发我们的顶级先导化合物，体内实验。