Therapeutic targeting of MYC interactions with an essential cofactor

MYC是人类癌症中最常被扩增的基因，其过度表达是一种 70%癌症中不同致癌信号通路突变的后果。vt.给出 作为癌症的驱动力，MYC的无处不在，有一个严重的未得到满足的需求，即开发出特定的 抑制MYC的药物具有抗癌治疗的作用。激活/转化- 结构域相关蛋白(TRRAP)是MYC的一个重要的核辅因子，而且很小 MYC：TRRAP相互作用的分子抑制剂被预测具有强大的抗癌作用 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物 MYC：TRRAP并发起与诺华生物医学研究所的合作 搜索他们的非专利50,000种类似药物的化合物集。我们确定了33种不同的 在纳米分子和微摩尔分子中对MYC：TRRAP显示抑制活性的化合物 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 确定这些化合物中哪些抑制天然MYC：TRRAP复合体和 确定它们与其他MYC和/或TRRAP相互作用蛋白的特异性。前景看好 化合物在三阴性乳腺癌中的生长抑制活性也将被检测。 细胞，它具有高水平的MYC，并决定是否可以将生长抑制归因于丢失 MYC功能。我们的长期目标是在临床前开发我们的顶级先导化合物 活体实验。

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.