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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，并且作为一种基因过度表达