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。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
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
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ 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:
相似国自然基金
Epac1/2通过蛋白酶体调控中性粒细胞NETosis和Apoptosis在急性肺损伤中的作用研究
- 批准号:LBY21H010001
- 批准年份:2020
- 资助金额:0.0 万元
- 项目类别:省市级项目
基于Apoptosis/Ferroptosis双重激活效应的天然产物AlbiziabiosideA的抗肿瘤作用机制研究及其结构改造
- 批准号:81703335
- 批准年份:2017
- 资助金额:20.0 万元
- 项目类别:青年科学基金项目
双肝移植后Apoptosis和pyroptosis在移植物萎缩差异中的作用和供受者免疫微环境变化研究
- 批准号:81670594
- 批准年份:2016
- 资助金额:58.0 万元
- 项目类别:面上项目
Serp-2 调控apoptosis和pyroptosis 对肝脏缺血再灌注损伤的保护作用研究
- 批准号:81470791
- 批准年份:2014
- 资助金额:73.0 万元
- 项目类别:面上项目
Apoptosis signal-regulating kinase 1是七氟烷抑制小胶质细胞活化的关键分子靶点?
- 批准号:81301123
- 批准年份:2013
- 资助金额:23.0 万元
- 项目类别:青年科学基金项目
APO-miR(multi-targeting apoptosis-regulatory miRNA)在前列腺癌中的表达和作用
- 批准号:81101529
- 批准年份:2011
- 资助金额:22.0 万元
- 项目类别:青年科学基金项目
放疗与细胞程序性死亡(APOPTOSIS)相关性及其应用研究
- 批准号:39500043
- 批准年份:1995
- 资助金额:9.0 万元
- 项目类别:青年科学基金项目
相似海外基金
Apoptosis regulation by RNA binding proteins
RNA 结合蛋白的细胞凋亡调节
- 批准号:
DDG-2015-00002 - 财政年份:2016
- 资助金额:
$ 40万 - 项目类别:
Discovery Development Grant
Apoptosis regulation by RNA binding proteins
RNA 结合蛋白的细胞凋亡调节
- 批准号:
DDG-2015-00002 - 财政年份:2015
- 资助金额:
$ 40万 - 项目类别:
Discovery Development Grant
Mechanisms Of RNA-Binding Protein-Mediated Apoptosis In Oral Mucositis
RNA结合蛋白介导的口腔粘膜炎细胞凋亡机制
- 批准号:
9237260 - 财政年份:2013
- 资助金额:
$ 40万 - 项目类别:
Mechanisms Of RNA-Binding Protein-Mediated Apoptosis In Oral Mucositis
RNA结合蛋白介导的口腔粘膜炎细胞凋亡机制
- 批准号:
8657030 - 财政年份:2013
- 资助金额:
$ 40万 - 项目类别:
Apoptosis regulation by RNA binding proteins
RNA 结合蛋白的细胞凋亡调节
- 批准号:
261206-2009 - 财政年份:2013
- 资助金额:
$ 40万 - 项目类别:
Discovery Grants Program - Individual
Mechanisms Of RNA-Binding Protein-Mediated Apoptosis In Oral Mucositis
RNA结合蛋白介导的口腔粘膜炎细胞凋亡机制
- 批准号:
8993725 - 财政年份:2013
- 资助金额:
$ 40万 - 项目类别:
Mechanisms Of RNA-Binding Protein-Mediated Apoptosis In Oral Mucositis
RNA结合蛋白介导的口腔粘膜炎细胞凋亡机制
- 批准号:
8503886 - 财政年份:2013
- 资助金额:
$ 40万 - 项目类别:
Apoptosis regulation by RNA binding proteins
RNA 结合蛋白的细胞凋亡调节
- 批准号:
261206-2009 - 财政年份:2012
- 资助金额:
$ 40万 - 项目类别:
Discovery Grants Program - Individual
The binding and apoptosis inhibitory action to germ cells of relaxin-like peptide expressed in the boar testis
公猪睾丸表达的松弛素样肽与生殖细胞的结合及凋亡抑制作用
- 批准号:
24580408 - 财政年份:2012
- 资助金额:
$ 40万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Identification of the Insulin-like Growth Factor 2 mRNA Binding Protein (IGF2BP1) as an important regulator of cIAP1 translation and apoptosis in Rhabdomyosarcomas
鉴定胰岛素样生长因子 2 mRNA 结合蛋白 (IGF2BP1) 作为横纹肌肉瘤中 cIAP1 翻译和细胞凋亡的重要调节因子
- 批准号:
269093 - 财政年份:2012
- 资助金额:
$ 40万 - 项目类别: