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

基本信息

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
项目类别：
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

项目摘要

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.

抽象的 MYC家族蛋白包括三个称为MYC（C-YC），N-YC和L-MYC的旁系同源物蛋白质通过调节细胞过程（例如基因转录，蛋白质翻译，细胞周期进程和细胞死亡。名称：mycn）通常在神经内分泌起源的肿瘤中发现 MYCN基因座的扩增发生在大约50％的高风险神经母细胞瘤最常见的颅外固体恶性肿瘤。激酶A：N-YC与Aurora激酶A结合，以“逃脱”蛋白酶体降解。激酶A抑制剂CD532，有效触发N-myc从Aurora激酶A，导致N-MYC蛋白 MyCN放大神经细胞的稳定和回归。概念分子，这种组合的溶解度差，渗透性有限，代谢稳定性差，使得这是一个较差的候选药物。有效地将N-YC从Aurora A分离并破坏N-MYC，并且比CD532更生物利用。为简单起见，这些组合作用称为“ N-MYC降解器”。我们I阶段建议的主要目标是提高效力，选择性，类似药物的特性和体内我们的N-YC DEGRADER的功效，SSTA-152。具体目标1。提高SSTA-152的效力和选择性。具体目标2。提高SSTA-152的药物样性能和体内功效。总体目标是开发用于治疗N-YC驱动的癌症的临床N-YC降解器，以实现A 患者的巨大需求。