Small Molecule N-myc Degraders as Novel Cancer Therapeutic Agents

摘要 MYC家族蛋白由三种旁系同源物组成，称为Myc（c-myc）、N-myc和L-myc。该MYC 蛋白质通过调节细胞过程在细胞增殖和肿瘤发生中起重要作用， 基因转录、蛋白质翻译、细胞周期进程和细胞死亡。高水平的N-myc蛋白（基因 MYCN）通常见于神经内分泌来源的肿瘤，已显示其可驱动肿瘤 增长MYCN基因座的扩增发生在大约50%的高危神经母细胞瘤中，这是神经母细胞瘤的主要特征。 最常见的儿童颅外实体恶性肿瘤。N-myc蛋白水平受Aurora高度调节 激酶A：N-myc与Aurora激酶A结合以“逃避”蛋白酶体降解。工具小分子极光 激酶A抑制剂CD 532有效地将N-myc从Aurora激酶A上解离，产生N-myc蛋白 MYCN扩增的神经母细胞瘤的不稳定和消退。虽然CD 532是一个很好的证明- 概念分子，这种化合物具有差的溶解性、有限的渗透性和差的代谢稳定性， 这是一个糟糕的候选药物。为了克服这些缺点，我们开发了独特的新型小分子， 有效地使N-myc与Aurora A解离并使N-myc不稳定，且比CD 532更具有生物利用度。 为简单起见，这些化合物被称为“N-myc降解剂”。 我们的第一阶段提案的主要目标是提高效力，选择性，药物样性质，以及体内 我们的主要N-myc降解剂SSTA-152的功效。我们提出两个具体目标： 具体目标1。提高SSTA-152的效力和选择性。 具体目标2。改善SSTA-152的药物样性质和体内功效。 总体目标是开发一种临床N-myc降解剂，用于治疗N-myc驱动的癌症，其实现了 患者的重大需求未得到满足。

ABSTRACT The MYC family proteins are comprised of three paralogs termed Myc (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. High levels of N-myc protein (gene name: MYCN) are often found in tumors of neuroendocrine origins, where it has been shown to drive tumor growth. Amplification of the MYCN locus occurs in approximately 50% of high-risk neuroblastoma, which is the most common extracranial solid malignancy of childhood. N-myc protein levels are highly regulated by Aurora kinase A: N-myc binds to Aurora kinase A to “escape” proteasomal degradation. The tool small molecule Aurora kinase A inhibitor, CD532, effectively dissociates N-myc from Aurora kinase A, resulting in N-myc protein destabilization and regression of MYCN-amplified neuroblastomas. Although CD532 is an excellent proof-of- concept molecule, this compound has poor solubility, limited permeability, and poor metabolic stability, making it a poor drug candidate. To overcome these liabilities, we have developed distinct, novel small molecules, that effectively dissociate N-myc from Aurora A and destabilize N-myc and that are more bioavailable than CD532. For simplicity, these compounds are referred to as “N-myc degraders”. The primary goal of our Phase I proposal is to improve the potency, selectivity, drug-like properties, and in vivo efficacy of our lead N-myc degrader, SSTA-152. We propose two specific aims: Specific Aim 1. Increase the potency and selectivity of SSTA-152. Specific Aim 2. Improve drug-like properties and in vivo efficacy of SSTA-152. The overall goal is to develop a clinical N-myc degrader for treating N-myc-driven cancers, which fulfills a significant unmet need in patients.