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:
- 金额:$ 40万
- 依托单位:
- 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:
- 关键词:AdultApoptosisBindingBiological AssayBiological MarkersCancer BiologyCastrationCell CycleCell Cycle ProgressionCell DeathCell LineCell ProliferationCell physiologyClinicalClinical TrialsComputer SimulationCrystallizationCytochrome P450Dose-LimitingDrug KineticsEmbryonic DevelopmentEtoposideGenesGenetic TranscriptionGoalsGrowthHomologous GeneHumanIn VitroIntellectual PropertyLaboratory ResearchLeadLegal patentLiver MicrosomesMYC Family ProteinMYCN geneMalignant Childhood NeoplasmMalignant NeoplasmsMeasuresMediatingMetabolicMolecular BiologyMolecular ConformationMusN-Myc ProteinNamesNeuroblastomaNeuroendocrine Prostate CancerNeuroendocrine TumorsNormal CellNude MiceOral AdministrationPatientsPermeabilityPharmaceutical ChemistryPharmaceutical PreparationsPhasePhosphotransferasesPlayPropertyProtein-Serine-Threonine KinasesProteinsPublishingRefractoryResistanceRoleS phaseSeriesSolidSolubilityStructureStructure-Activity RelationshipSurvival RateSynthesis ChemistryTherapeutic AgentsTissuesToxic effectTranslationsanalogaurora kinase Ac-myc Genescancer cellcancer survivalchemotherapydrug candidateefficacy studyfunctional groupgenotoxicityhigh riskimprovedin vivoinhibitormulticatalytic endopeptidase complexneuroblastoma cellnovelparalogous genepreclinical developmentsmall moleculestandard of caretooltumortumor growthtumor xenografttumorigenesis
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.
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。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Dennis Liang Fei其他文献
G protein Gαi functions immediately downstream of Smoothened in Hedgehog signalling
G 蛋白 Gαi 在 Hedgehog 信号通路中在平滑蛋白的下游立即发挥作用。
- DOI:
10.1038/nature07459 - 发表时间:
2008-11-05 - 期刊:
- 影响因子:48.500
- 作者:
Stacey K. Ogden;Dennis Liang Fei;Neal S. Schilling;Yashi F. Ahmed;John Hwa;David J. Robbins - 通讯作者:
David J. Robbins
Dennis Liang Fei的其他文献
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{{ truncateString('Dennis Liang Fei', 18)}}的其他基金
Small Molecule MYC Degraders as Novel Cancer Therapeutic Agents
小分子 MYC 降解剂作为新型癌症治疗剂
- 批准号:
10766504 - 财政年份:2022
- 资助金额:
$ 40万 - 项目类别:
Development of Notch1-selective Small Molecule Inhibitor for the Treatment of Cancer
用于治疗癌症的Notch1选择性小分子抑制剂的开发
- 批准号:
10478196 - 财政年份:2021
- 资助金额:
$ 40万 - 项目类别:
Small Molecule Inhibitors of Notch Activation Complex Kinase (NACK) as Novel Cancer Therapeutic Agents
Notch 激活复合激酶 (NACK) 小分子抑制剂作为新型癌症治疗剂
- 批准号:
10010409 - 财政年份:2020
- 资助金额:
$ 40万 - 项目类别:
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