Small Molecule MYC Degraders as Novel Cancer Therapeutic Agents

项目摘要/摘要 MYC家族蛋白由c-myc、N-myc和L-myc三个类似蛋白组成。MYC蛋白 通过调节基因等细胞过程，在细胞增殖和肿瘤发生中发挥基础性作用 转录、蛋白质翻译、细胞周期进程和细胞死亡。N-Myc和L-Myc开车 在少数癌症类型中，c-myc的要求在广泛的 人类癌症。Aurora A高度调控myc蛋白水平：c-myc和N-myc都与Aurora结合 激酶A“逃脱”蛋白酶体降解。在SBIR第一阶段的支持下，我们成功地确定了 新的小分子，1)。直接针对MYC：Aurora A绑定接口，2)。有力地贬低了这两个 内源N-myc和c-myc(下称“myc降解物”)，3)。新陈代谢稳定，口服 生物利用度；4)。能有效抑制依赖N-myc或c-myc的肿瘤生长。 在SBIR第二阶段，我们计划通过一种 重点治疗c-myc依赖型癌症。我们提出两个具体目标： 具体目标1：测试SSTA-315在平行发展的c-myc依赖肿瘤中的疗效 衍生的c-myc降解剂具有更高的效力和疗效。 具体目标2：评估SSTA-315(或替代的MYC降解剂)在启用IND方面的安全性 GLP毒性研究。 成功完成拟议的研究将完成我们的牵头MYC的IND安全研究 降解器，准备在FDA注册IND作为下一步。鉴于MYC蛋白 在大多数人类癌症中，我们的MYC降解者可能会影响数百万人的生活 在美国的癌症患者和代表了一个重要的市场机会。

PROJECT SUMMARY/ABSTRACT The MYC family proteins are comprised of three paralogs termed c-myc, N-myc, and L-myc. The MYC proteins play a fundamental role in cell proliferation and oncogenesis by regulating cellular processes such as gene transcription, protein translation, cell cycle progression, and cell death. While N-myc and L-myc drive oncogenesis in a small number of cancer types, the requirement of c-myc is widespread in a broad range of human cancers. MYC protein levels are highly regulated by Aurora A: both c-myc and N-myc bind to Aurora kinase A to “escape” proteasomal degradation. With the support of SBIR Phase I, we have successfully identified novel small molecules that 1). directly target the MYC:Aurora A binding interface, 2). potently degrade both endogenous N-myc and c-myc (henceforth “MYC degraders”), 3). are metabolically stable and orally bioavailable, and 4). are efficacious in inhibiting the growth of tumors dependent on either N-myc or c-myc. For the SBIR Phase II period, we plan to advance pre-clinical development of our MYC degraders with an emphasis on treating c-myc-dependent cancers. We propose two specific aims: Specific Aim 1: Test the efficacy of SSTA-315 across c-myc dependent cancers, while in parallel develop derivative c-myc degraders with improved potency and efficacy. Specific Aim 2: Evaluate the safety profile of SSTA-315 (or an alternative lead MYC degrader) in IND-enabling GLP toxicity studies. Successful completion of the proposed studies will complete IND-enabling safety studies for our lead MYC degrader, preparing for the IND registration with the FDA as the immediate next step. Given that MYC proteins are deregulated in most human cancers, our MYC degraders have potential to impact the lives of millions of cancer patients in U.S. and represent a significant market opportunity.