Design of a Covalent Inhibitor for c-Myc-Dependent Cancers

描述(由申请人提供)：我们公司的主要商业目标是开发抑制人类癌基因c-Myc的新疗法。C-Myc是一种主要的人类癌基因，据估计，在所有人类癌症中，至少有70%是由c-Myc基因引起的，其中大多数癌症是侵袭性的，对目前的治疗效果很差。尽管进行了30多年的研究，但抑制c-Myc的药物开发一直没有成功，因为这种蛋白质是一种转录因子，缺乏小分子结合的口袋。因此，开发抑制c-Myc的新型治疗方法被认为是推进癌症治疗的最重要目标之一。最近，包括我们在内的几个实验室的研究表明，小的泛素样修饰(SUMO)在c-Myc依赖的肿瘤发生中起关键作用。我们最初的研究集中在结直肠癌上，因为这些癌症几乎100%依赖于c-Myc，转移性结直肠癌迫切需要新的治疗方法来提高患者的生存率。结直肠癌中c-Myc表达的转录因子--β-连环蛋白/Tcf-4通过苏莫化对c-Myc的表达起重要作用。在初步研究中，我们已经使用高通量筛选确定了SAE的一个非常特异和有效的抑制支架，SAE是催化相扑修饰的活化酶。用该抑制剂抑制糖基化或通过敲除SAE可显著降低结直肠癌细胞中c-Myc的水平。根据我们最近发现的先导化合物的新作用机制，我们设计了提高先导化合物效力的策略，这表明了一种容易处理的方法来提高其特异性、效力和作用时间。然后，我们将确定改进后的化合物的特异性和细胞机制，并将在动物模型中进行毒性和疗效研究。我们的结果将大大推进这一领域的发展 首次在动物模型中证实SUMO化是抑制c-Myc癌基因的潜在靶点。

DESCRIPTION (provided by applicant): The leading commercial goal of our company is to develop novel therapeutics to inhibit the human oncogene, c-Myc. C-Myc is a major human oncogene that is estimated to contribute to at least 70% of all human cancers, most of which are aggressive and respond poorly to current therapies. Despite more than 30 years of research, the development of drugs that inhibit c-Myc has been unsuccessful because the protein is a transcription factor that lacks pockets for small molecules to bind. Therefore, developing novel treatments that inhibit c-Myc is considered one of the most important goals for advancing cancer therapeutics. Recently studies from several laboratories including ours have shown that the small ubiquitin-like modifications (SUMO) are critical for c-Myc-dependent tumorigenesis. Our initial studies are focused on colorectal cancers, because these cancers are almost 100% dependent on c-Myc and new therapies are critically needed for metastatic colorectal cancers to improve patient survival. SUMOylation is important for c-Myc expression through activation of beta-catenin/Tcf-4, the transcription factor for c-Myc expression in colorectal cancers. In preliminary studies, we have identified a very specific and potent inhibitor scaffold of SAE, the activating enzyme that catalyzes SUMO modifications, using high throughput screening. Inhibition of SUMOylation with this inhibitor or by knockdown of SAE dramatically reduced c-Myc level in colorectal cancer cells. We have designed strategies to improve the potency of the lead compound based on our recent discovery of its novel mechanism of action, which indicates a tractable approach to increase its specificity, potency and duration of action. We will then determine the specificity and cellular mechanisms of the improved compounds and will conduct toxicity and efficacy studies in animal models. Our results will significantly advance the field by providing the first proof-of-concept in animal models that SUMOylation is a potential target to inhibit the c-Myc oncogene.