Project 3: Targeting MYC in CRC

项目摘要/摘要：P3。瞄准MYC 结直肠癌(CRC)反复遗传扰动激活癌基因转录因子MYC 这在人类癌症中占有突出的地位。尽管MYC在CRC中的广泛参与，以及 研究表明，MYC的基因抑制促进了小鼠模型肿瘤的直接消退 系统，MYC通常被认为是不可用药。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，我们提出了一种新的范例 MYC的靶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 染色质支架蛋白WDR5，它与MYC广泛共存于整个基因组，并促进 MYC与靶基因结合。结构分析表明，MYC通过与WDR5结合的浅层， WDR5表面有疏水裂隙，非常适合药物发现。这个项目的目标是 瞄准MYC-WDR5接口以发现一种药物，该药物将通过阻止 MYC与靶基因染色质的稳定结合。该项目结合了药物发现、结构生物学、 药物化学、生物化学和尖端基因组学方法，以及强大的模型系统， 鉴定、提纯和验证破坏MYC-WDR5相互作用的类药物分子，并探索其 作为抗癌药物对抗结直肠癌的有效性。在五年的资助期内，我们打算生产 一流的MYC-WDR5抑制剂，将充分验证其在治疗CRC中的有效性，并准备 继续进行研究性新药(IND)使能研究。该项目的成功完成将解决 对靶向抗MYC疗法的明确的未得到满足的临床需求，该疗法有望对 只有有限的治疗选择的癌。在该计划中发现的药物可能也会有 对多种癌症类型的效用。

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.