Project 3: Targeting MYC in CRC

项目总结/摘要：P3。针对MYC 结直肠癌（CRC）中复发性遗传扰动激活MYC，一种致癌转录因子 在人类癌症中的显著特征。尽管马来西亚基督教青年会广泛参与儿童权利委员会的工作， 研究表明MYC的遗传抑制促进小鼠模型中的明显肿瘤消退 系统，MYC通常被认为是不可用的。事实上，目前还没有类似药物的分子 能够直接阻断癌细胞中的MYC功能。然而，最近，我们提出了一个新的范例， MYC靶向基因识别也为发现阻断MYC功能的药物创造了新的机会。 我们发现MYC与染色质的稳定结合依赖于它与染色质的直接相互作用。 染色质支架蛋白WDR 5，其与MYC在整个基因组中广泛共定位，并促进 MYC与靶基因的结合。结构分析显示，MYC通过接合一个浅的， WDR 5表面上的疏水裂缝非常适合药物发现。该项目的目标是 目标是MYC-WDR 5接口，以发现一种药物，通过阻止 MYC与靶基因染色质稳定结合。这个项目结合了药物发现，结构生物学， 药物化学、生物化学和尖端的基因组方法，沿着强大的模型系统， 鉴定、改进和验证破坏MYC-WDR 5相互作用的药物样分子，并探索其 作为抗CRC的抗癌剂的有效性。在五年的资助期内，我们计划 一流的MYC-WDR 5抑制剂，将充分验证其在治疗CRC中的效用，并准备 继续进行新药临床试验（IND）启动研究。该项目的成功完成将解决 靶向抗MYC治疗的明确未满足的临床需求，预期对 只有有限的治疗选择的CRC。在这个项目中发现的药物也可能有 对广泛的癌症类型的效用。

PROJECT SUMMARY/ABSTRACT: P3. Targeting MYC Recurring genetic perturbations in colorectal cancer (CRC) activate MYC, an oncogenic transcription factor that features prominently in human cancer. Despite the pervasive involvement of MYC in CRC, and a wealth of studies demonstrating that genetic inhibition of MYC promotes frank tumor regression in mouse model systems, MYC is generally considered undruggable. Indeed, there are currently no drug-like molecules capable of directly blocking MYC function in cancer cells. Recently, however, we presented a new paradigm for target gene recognition by MYC that also created a new opportunity to discover drugs that block MYC function. We found that the stable association of MYC with chromatin depends on its direct interaction with the chromatin scaffolding protein WDR5, which co-localizes broadly with MYC across the genome and facilitates MYC binding to target genes. Structural analysis revealed that MYC binds WDR5 by engaging a shallow, hydrophobic cleft on the surface of WDR5 that is well-suited for drug discovery. The goal of this project is to target the MYC–WDR5 interface to discover a drug that will disable MYC function in CRC by preventing the stable association of MYC with target gene chromatin. This project combines drug discovery, structural biology, medicinal chemistry, biochemistry, and cutting-edge genomic approaches, along with powerful model systems, to identify, refine, and validate drug-like molecules that disrupt the MYC-WDR5 interaction, and to explore their effectiveness as anti-cancer agents against CRC. Within the five year funding period, we intend to produce first-in-class MYC–WDR5 inhibitors that will be fully validated for their utility in treating CRC and ready to proceed to Investigational New Drug (IND)-enabling studies. Successful completion of this project will address a clear unmet clinical need for targeted anti-MYC therapies, which are expected to have broad efficacy against CRCs for which there are only limited treatment options. Drugs discovered in this program will likely also have utility against a wide spectrum of cancer types.