Project 3: Targeting MYC in CRC
项目 3:针对 CRC 中的 MYC
基本信息
- 批准号:10218111
- 负责人:
- 金额:$ 32.2万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-07-09 至 2024-05-31
- 项目状态:已结题
- 来源:
- 关键词:APC mutationAcuteAddressAffinityAnimalsAntineoplastic AgentsAttenuatedBindingBinding ProteinsBiochemistryBiologicalBiological MarkersBiological ModelsCancer CenterCancer ModelCellsCharacteristicsChromatinClinicalClinical TrialsColorectal CancerDoseDrug DesignDrug KineticsDrug or chemical Tissue DistributionEffectivenessEnsureFunctional disorderFundingGenesGeneticGenomeGenomic approachGoalsHumanHydrophobicityIn VitroInvestigational DrugsKRAS2 geneLeadMalignant NeoplasmsMalignant neoplasm of gastrointestinal tractMaximum Tolerated DoseModelingMolecularMolecular AnalysisMonitorMusMutationOncogenicOncoproteinsOutcomePharmaceutical ChemistryPharmaceutical PreparationsPharmacodynamicsPharmacologyPlayPropertyResourcesRoleSafetyScaffolding ProteinSeriesSiteStructureSurfaceTimeToxicokineticsVariantbasecancer cellcancer typecandidate markerclinical candidatecolon cancer cell linecolon cancer patientscolon tumorigenesiscolorectal cancer preventioncolorectal cancer treatmentdrug discoverydrug metabolismefficacy testingefficacy validationimprovedin vivoin vivo evaluationinhibitor/antagonistinnovationmouse modelnanomolaroverexpressionpatient derived xenograft modelpharmacodynamic biomarkerpre-clinicalpreclinical safetypreventprogramsresearch clinical testingresponsesafety assessmentsmall moleculestructural biologytooltranscription factortumortumorigenic
项目摘要
PROJECT SUMMARY/ABSTRACT: P3. Targeting MYC
Recurring genetic perturbations in colorectal cancer (CRC) activate MYC, an oncogenic transcription factor
that features prominently in human cancer. Despite the pervasive involvement of MYC in CRC, and a wealth of
studies demonstrating that genetic inhibition of MYC promotes frank tumor regression in mouse model
systems, MYC is generally considered undruggable. Indeed, there are currently no drug-like molecules
capable of directly blocking MYC function in cancer cells. Recently, however, we presented a new paradigm for
target gene recognition by MYC that also created a new opportunity to discover drugs that block MYC function.
We found that the stable association of MYC with chromatin depends on its direct interaction with the
chromatin scaffolding protein WDR5, which co-localizes broadly with MYC across the genome and facilitates
MYC binding to target genes. Structural analysis revealed that MYC binds WDR5 by engaging a shallow,
hydrophobic cleft on the surface of WDR5 that is well-suited for drug discovery. The goal of this project is to
target the MYC–WDR5 interface to discover a drug that will disable MYC function in CRC by preventing the
stable association of MYC with target gene chromatin. This project combines drug discovery, structural biology,
medicinal chemistry, biochemistry, and cutting-edge genomic approaches, along with powerful model systems,
to identify, refine, and validate drug-like molecules that disrupt the MYC-WDR5 interaction, and to explore their
effectiveness as anti-cancer agents against CRC. Within the five year funding period, we intend to produce
first-in-class MYC–WDR5 inhibitors that will be fully validated for their utility in treating CRC and ready to
proceed to Investigational New Drug (IND)-enabling studies. Successful completion of this project will address
a clear unmet clinical need for targeted anti-MYC therapies, which are expected to have broad efficacy against
CRCs for which there are only limited treatment options. Drugs discovered in this program will likely also have
utility against a wide spectrum of cancer types.
项目摘要/摘要:P3。针对MYC
结直肠癌(CRC)的遗传扰动激活MYC,这是一种致癌转录因子
这在人类癌症中突出。尽管MYC在CRC中普遍存在,而且很多
研究表明,遗传抑制MYC会促进小鼠模型中的弗兰克肿瘤消退
系统,MYC通常被认为是不可能的。确实,目前没有类似药物的分子
能够直接阻止癌细胞中的MYC功能。但是,最近,我们提出了一个新的范式
MYC的靶基因识别也创造了一个新的机会来发现阻止MYC功能的药物。
我们发现,MYC与染色质的稳定关联取决于其直接相互作用
染色质脚手架蛋白WDR5,该蛋白质与MYC在基因组上广泛合作并促进
MYC与靶基因结合。结构分析表明,MYC通过与浅层,
适合于药物发现的WDR5表面上的疏水性裂缝。这个项目的目标是
靶向MYC – WDR5接口,以发现一种可以通过防止CRC禁用MYC功能的药物
MYC与靶基因染色质的稳定关联。该项目结合了药物发现,结构生物学,
药物化学,生物化学和尖端基因组方法以及强大的模型系统,
识别,完善和验证破坏MYC-WDR5相互作用的药物样分子,并探索它们
作为反对CRC的抗癌药物的有效性。在五年的资金期内,我们打算生产
一流的MYC – WDR5抑制剂,这些抑制剂将全面验证,以治疗CRC并准备好
继续研究新药(IND) - 增强研究。该项目的成功完成将解决
对靶向抗MYC疗法的明显未满足的临床需求,预计将具有广泛的效率
CRC仅有有限的治疗选择。在该计划中发现的药物也可能会有
针对各种癌症类型的实用程序。
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 }}
Robert Daniel Beauchamp其他文献
TGF-B1 enhances ras-mediated invasiveness in intestinal epithelial cells
- DOI:
10.1016/s0016-5085(00)84366-8 - 发表时间:
2000-04-01 - 期刊:
- 影响因子:
- 作者:
Koji Fujimoto;Debabrata Saba;Michihiko Wada;Hongmiao Sheng;Jinyi Shao;Robert Daniel Beauchamp - 通讯作者:
Robert Daniel Beauchamp
Robert Daniel Beauchamp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('Robert Daniel Beauchamp', 18)}}的其他基金
SMAD4 regulation of colon epithelial cell inflammatory responses
SMAD4对结肠上皮细胞炎症反应的调节
- 批准号:
10192679 - 财政年份:2019
- 资助金额:
$ 32.2万 - 项目类别:
Integrative prediction models for metastasis risk in colon cancer
结肠癌转移风险的综合预测模型
- 批准号:
9213912 - 财政年份:2016
- 资助金额:
$ 32.2万 - 项目类别:
Integrative prediction models for metastasis risk in colon cancer
结肠癌转移风险的综合预测模型
- 批准号:
8706083 - 财政年份:2012
- 资助金额:
$ 32.2万 - 项目类别:
Integrative prediction models for metastasis risk in colon cancer
结肠癌转移风险的综合预测模型
- 批准号:
8876370 - 财政年份:2012
- 资助金额:
$ 32.2万 - 项目类别:
Integrative prediction models for metastasis risk in colon cancer
结肠癌转移风险的综合预测模型
- 批准号:
8235376 - 财政年份:2012
- 资助金额:
$ 32.2万 - 项目类别:
Integrative prediction models for metastasis risk in colon cancer
结肠癌转移风险的综合预测模型
- 批准号:
8517624 - 财政年份:2012
- 资助金额:
$ 32.2万 - 项目类别:
相似国自然基金
阿魏酸基天然抗氧化抗炎纳米药物用于急性肾损伤诊疗一体化研究
- 批准号:82302281
- 批准年份:2023
- 资助金额:30 万元
- 项目类别:青年科学基金项目
SGO2/MAD2互作调控肝祖细胞的细胞周期再进入影响急性肝衰竭肝再生的机制研究
- 批准号:82300697
- 批准年份:2023
- 资助金额:30 万元
- 项目类别:青年科学基金项目
基于hemin-MOFs的急性心肌梗塞标志物负背景光电化学-比色双模分析
- 批准号:22304039
- 批准年份:2023
- 资助金额:30 万元
- 项目类别:青年科学基金项目
RNA甲基转移酶NSUN2介导SCD1 mRNA m5C修饰调控急性髓系白血病细胞铁死亡的机制研究
- 批准号:82300173
- 批准年份:2023
- 资助金额:30 万元
- 项目类别:青年科学基金项目
基于IRF5/MYD88信号通路调控巨噬细胞M1极化探讨针刀刺营治疗急性扁桃体炎的机制研究
- 批准号:82360957
- 批准年份:2023
- 资助金额:30 万元
- 项目类别:地区科学基金项目
相似海外基金
Roles for Adenomatous polyposis coli in colon injury prevention and wound healing
腺瘤性大肠杆菌在预防结肠损伤和伤口愈合中的作用
- 批准号:
10707443 - 财政年份:2022
- 资助金额:
$ 32.2万 - 项目类别:
Mechanistic dissection and inhibitor targeting of autophagy in RAS driven cancers
RAS 驱动的癌症中自噬的机制剖析和抑制剂靶向
- 批准号:
10432054 - 财政年份:2020
- 资助金额:
$ 32.2万 - 项目类别:
Mechanistic dissection and inhibitor targeting of autophagy in RAS driven cancers
RAS 驱动的癌症中自噬的机制剖析和抑制剂靶向
- 批准号:
10200721 - 财政年份:2020
- 资助金额:
$ 32.2万 - 项目类别:
Mechanistic dissection and inhibitor targeting of autophagy in RAS driven cancers
RAS 驱动的癌症中自噬的机制剖析和抑制剂靶向
- 批准号:
10658871 - 财政年份:2020
- 资助金额:
$ 32.2万 - 项目类别:
The Huwe1 ubiquitin ligase regulates mitosis, genomic stability and oncogenesis.
Huwe1 泛素连接酶调节有丝分裂、基因组稳定性和肿瘤发生。
- 批准号:
10188467 - 财政年份:2019
- 资助金额:
$ 32.2万 - 项目类别: