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，并且作为一种过度表达的基因 70% 的癌症中不同致癌信号通路突变的结果。给定由于 MYC 作为癌症驱动因素的普遍存在，因此迫切需要开发特定的抑制 MYC 功能的药物作为抗癌疗法。转录激活/转化- 结构域相关蛋白 (TRRAP) 是 MYC 必需的核辅因子，并且小 MYC:TRRAP 相互作用的分子抑制剂预计具有有效的抗癌作用活动。我们开发了一种基于荧光素酶的检测方法来鉴定小分子抑制剂 MYC:TRRAP 并与诺华生物医学研究所发起合作搜索他们的非专有 50,000 种类药化合物集。我们确定了 33 个不同的对 MYC:TRRAP 在纳摩尔至微摩尔范围内表现出抑制活性的化合物使用我们的荧光素酶测定的浓度范围。我们建议使用细胞和分子测定这些化合物中哪些会抑制天然 MYC:TRRAP 复合物，确定它们对于其他 MYC 和/或 TRRAP 相互作用蛋白的特异性。有前途还将分析化合物对三阴性乳腺癌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。长期目标是我们的顶级先导化合物的临床前开发体内实验。