Therapeutic targeting of MYC interactions with an essential cofactor

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。

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.