Small Molecule N-myc Degraders as Novel Cancer Therapeutic Agents

小分子 N-myc 降解剂作为新型癌症治疗剂

• 批准号: 10484078
• 负责人: Dennis Liang Fei
• 金额: $ 40万
• 依托单位: STEMSYNERGY THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-05 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10484078
• 关键词: Adult; Apoptosis; Binding; Biological Assay; Biological Markers; Cancer Biology; Castration; Cell Cycle; Cell Cycle Progression; Cell Death; Cell Line; Cell Proliferation; Cell physiology; Clinical; Clinical Trials; Computer Simulation; Crystallization; Cytochrome P450; Dose-Limiting; Drug Kinetics; Embryonic Development; Etoposide; Genes; Genetic Transcription; Goals; Growth; Homologous Gene; Human; In Vitro; Intellectual Property; Laboratory Research; Lead; Legal patent; Liver Microsomes; MYC Family Protein; MYCN gene; Malignant Childhood Neoplasm; Malignant Neoplasms; Measures; Mediating; Metabolic; Molecular Biology; Molecular Conformation; Mus; N-Myc Protein; Names; Neuroblastoma; Neuroendocrine Prostate Cancer; Neuroendocrine Tumors; Normal Cell; Nude Mice; Oral Administration; Patients; Permeability; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase; Phosphotransferases; Play; Property; Protein-Serine-Threonine Kinases; Proteins; Publishing; Refractory; Resistance; Role; S phase; Series; Solid; Solubility; Structure; Structure-Activity Relationship; Survival Rate; Synthesis Chemistry; Therapeutic Agents; Tissues; Toxic effect; Translations; analog; aurora kinase A; c-myc Genes; cancer cell; cancer survival; chemotherapy; drug candidate; efficacy study; functional group; genotoxicity; high risk; improved; in vivo; inhibitor; multicatalytic endopeptidase complex; neuroblastoma cell; novel; paralogous gene; preclinical development; small molecule; standard of care; tool; tumor; tumor growth; tumor xenograft; tumorigenesis

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.

摘要 MYC家族蛋白由三个类似蛋白组成，分别为Myc(c-myc)、N-myc和L-myc。MYC 蛋白质在细胞增殖和肿瘤发生中起重要作用，它通过调节细胞过程，如 基因转录、蛋白质翻译、细胞周期进程和细胞死亡。高水平的N-myc蛋白(基因 名称：MYCN)经常发现于神经内分泌源性肿瘤，已被证明是肿瘤的驱动力 成长。MYCN基因扩增发生在大约50%的高危神经母细胞瘤中，这是 儿童期最常见的颅外实体恶性肿瘤。N-myc蛋白水平受极光高度调控 蛋白激酶A：N-myc与极光蛋白A结合，“逃避”蛋白酶体的降解。工具小分子极光 激酶A抑制剂CD532有效地将N-myc从极光激酶A中分离出来，从而产生N-myc蛋白 MYCN扩增的神经母细胞瘤的不稳定和消退。尽管CD532是一种出色的 概念分子，该化合物溶解性差，渗透性有限，代谢稳定性差，使 这是一个糟糕的候选药物。为了克服这些缺陷，我们开发了独特的、新颖的小分子， 有效地将N-myc与Aurora A解离并破坏N-myc的稳定性，这些N-myc比CD532更具生物利用度。 为简单起见，这些化合物被称为“N-myc降解剂”。 我们第一阶段提案的主要目标是提高效力、选择性、类药物特性和体内 我们的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。 具体目的2.改善SSTA-152的类药物性质和体内疗效。 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，它实现了 患者的重大未得到满足的需求。