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：
10655655
负责人：
MICHAEL David COLE
金额：
$ 18.78万
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 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10655655
关键词：
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 Lead Leucine Zippers Luciferases MYC Family Protein Malignant Neoplasms Mass Spectrum Analysis Measurement Molecular Multienzyme Complexes Mutation Nuclear Nuclear Protein Oncogenic Pharmaceutical Preparations Predisposition Proliferating Protein Inhibition Proteins Series Signal Pathway Specificity TRRAP gene Therapeutic Transactivation anti-cancer therapeutic anticancer activity cancer cell cancer therapy cell growth cofactor drug-like compound experimental study histone modification in vivo inhibitor metaplastic cell transformation nanomolar novel oncogene addiction overexpression preclinical development protein complex protein function protein protein interaction 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是人类癌症中最常放大的基因，过表达 70％的癌症中各种致癌信号通路突变的结果。给出 MYC作为癌症驱动力的无处不在，有至关重要的未满足的需求抑制MYC作为抗癌治疗剂的药物。反式激活/转化 - 域相关蛋白（TRRAP）是MYC的必需核辅助因子，而小 MYC：TRRAP相互作用的分子抑制剂预计具有有效的抗癌药活动。我们开发了一种基于萤光素酶的测定法，以鉴定小分子抑制剂 MYC：TRRAP并与诺华生物医学研究所合作开始搜索其非专有的50,000种药物样化合物。我们确定了33种不同的在纳摩尔到微摩尔中显示MYC：TRRAP的抑制活性的化合物使用我们的荧光素酶测定法。我们建议使用细胞和分子确定哪种化合物抑制天然MYC的测定法：TRRAP复合物和确定它们对其他MYC和/或TRRAP相互作用蛋白的特异性。有希望的还将分析化合物在三重阴性乳腺癌中的生长抑制活性细胞，其具有较高的MYC并确定生长抑制是否可以归因于损失 MYC功能。一个长期目标是我们顶级铅化合物的临床前开发体内实验。