Small Molecule MYC Degraders as Novel Cancer Therapeutic Agents

项目总结/摘要 MYC家族蛋白由三种旁系同源物组成，称为c-myc、N-myc和L-myc。MYC蛋白 在细胞增殖和肿瘤发生中起重要作用，通过调节细胞过程，如基因 转录、蛋白质翻译、细胞周期进程和细胞死亡。而N-myc和L-myc驱动 在少数癌症类型中，c-myc的需求在广泛的癌症类型中广泛存在。 人类癌症MYC蛋白水平受Aurora A高度调节：c-myc和N-myc均与Aurora结合 激酶A以“逃避”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）。直接靶向MYC：Aurora A结合界面，2）。会使两者都退化 内源性N-myc和c-myc（以下称为“MYC降解剂”），3）。代谢稳定， 生物可利用性，以及4）。有效抑制依赖于N-myc或c-myc的肿瘤生长。 对于SBIR II期，我们计划推进MYC降解剂的临床前开发， 强调治疗c-myc依赖性癌症。我们提出两个具体目标： 具体目标1：测试SSTA-315在c-myc依赖性癌症中的功效，同时平行开发 衍生的c-myc降解剂，其具有改进的效力和功效。 具体目标2：评价SSTA-315（或替代的主要MYC降解剂）在IND启用中的安全性 GLP毒性研究。 成功完成拟定研究将完成我们的主要MYC的IND使能安全性研究 降解剂，准备与FDA的IND注册作为立即的下一步。鉴于MYC蛋白 在大多数人类癌症中，我们的MYC降解剂有可能影响数百万人的生活， 美国的癌症患者，这是一个巨大的市场机会。

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.