Reposition and Optimization of Deferiprone for Breast Cancer Therapy
去铁酮在乳腺癌治疗中的重新定位和优化
基本信息
- 批准号:10209415
- 负责人:
- 金额:$ 50.54万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-03-01 至 2026-02-28
- 项目状态:未结题
- 来源:
- 关键词:4T1ApoptosisBackBioinformaticsBreast Cancer CellBreast Cancer cell lineBreast Cancer therapyBreast CarcinomaCancer Cell GrowthCancer EtiologyCell SurvivalCellsCessation of lifeChemopreventionClinicalDataDrug KineticsDrug resistanceEndocrineEpidermal Growth Factor ReceptorEpigenetic ProcessEstrogen Receptor ModulatorsEstrogen Receptor alphaEstrogen ReceptorsExhibitsFDA approvedFamilyFinancial compensationFulvestrantFunctional disorderHeterochromatinHistone DeacetylaseHistonesHormonesHumanIn VitroIncidenceInvestigationIron Chelating AgentsKDM5B geneLeadLysineMDA MB 231Malignant NeoplasmsMalignant neoplasm of lungMeasuresMediatingMedicalModalityModelingNeoplasm MetastasisOxidasesPatientsPharmaceutical PreparationsPharmacodynamicsPharmacologyProgesterone ReceptorsPropertyProteinsReaderReceptor SignalingRelapseResistanceRoleSelective Estrogen Receptor ModulatorsSignal TransductionT47DTailTamoxifenTestingTherapeutic AgentsTherapeutic InterventionToxicologyVeinsWomanXenograft procedurebasecancer subtypesclinical developmentcytotoxiccytotoxicitydesigngene repressionhistone methyltransferasein vivoinhibitor/antagonistinsightlead candidatemalignant breast neoplasmmembermouse modelneoplastic cellnovelnovel therapeuticsparalogous genepreclinical studyreceptor expressionsuccesstargeted treatmenttriple-negative invasive breast carcinomatumortumor growth
项目摘要
Project Summary/Abstract: In 2020 there will be ~ 276,480 estimated new cases of invasive breast cancer
(BCa) among women in the US, causing an estimated ~ 42,170 deaths. Two common mechanisms for the
sustenance of BCa are epigenetic dysfunction and the malfunction of endocrine proteins such as estrogen
receptor (ER). The specific focus of the studies proposed in this application is to repurpose deferiprone (Def),
an FDA-approved iron chelator, as a template for the discovery of novel histone lysine demethylase (KDM)
inhibitors optimized for BCa therapy. Most compounds that have been or are being developed clinically exhibit
greater efficacy for a subtype of BCa. In this regard, therapeutic interventions that capitalize on ER signaling
malfunctions, a driver of more than 70% of BCas, have enjoyed measured success in BCa therapy and/or chemo-
prevention. However, despite initial benefits, most patients eventually relapse due to acquired resistance to these
drugs. Additionally, there are no targeted treatment options for triple-negative breast cancer (TNBC), a BCa
subtype lacking ER, Human Epidermal Growth Factor receptor 2 (HER2), and Progesterone Receptor (PR) and
which accounts for over 20% of BCa incidence. Therefore, there is an unmet medical need for increasingly
selective and potent drugs to treat early and resistant stages of all BCa subtypes.
BCa viability, regardless of ER expression status, depends on an extensive network of epigenetic
modifiers - histone mark writers, readers and erasers. Bioinformatic and functional analysis have identified
specific subfamilies of the amino oxidase and Jumonji family of histone lysine demethylases (KDMs), histone
methyltransferases (HMTs) and histone deacetylase (HDACs) as essential in supporting ERα signaling
activation. Among these epigenetic modifiers, KDM1, KDM3A, KDM5A, KDM5B and KDM6A are exquisitely
wired into ERα signaling and are collectively vital for BCa cell viability. Moreover, studies have implicated KDMs
such as KDM6A in other ER-independent epigenetic reprograming which sustains TNBC as well. Unlike ERα
signaling, pharmacological inhibition of KDMs has not been clinically validated. Although inhibition of KDM3A,
KDM5A, KDM5B and KDM6A caused BCa cells growth arrest in vitro and in vivo, there are however precedents
for compensation among KDM paralogs in tumor models generated by selective deletion of a paralog member.
This study hypothesizes that collective inhibition of KDM paralogs implicated in BCa etiology will blunt the
possibility of compensation among KDM paralogs that could occur from paralog selective inhibition, resulting in
novel selective and potent drugs to treat BCa regardless of the cell ER expression status. The proposed study
is designed to test this hypothesis. The specific aims are: 1) Develop Def-based KDM inhibitors with favorable
toxicological and pharmacokinetic (PK) properties. 2) Characterize the correlation between intracellular on-target
effects (pharmacodynamics) and whole cell antiproliferative activity. 3) Investigate the in vivo efficacy of lead
compounds in five BCa murine models.
项目摘要/摘要:2020年,估计将有约276,480例浸润性乳腺癌新发病例
(BCa)在美国的妇女中,估计造成约42,170人死亡。两种常见的机制
BCa的维持是表观遗传功能障碍和雌激素等内分泌蛋白的功能障碍
受体(ER)。本申请中提出的研究的具体焦点是重新利用去铁酮(Def),
FDA批准的铁螯合剂,作为发现新型组蛋白赖氨酸脱甲基酶(KDM)的模板
针对BCa治疗优化的抑制剂。大多数已经或正在临床开发的化合物表现出
对BCa亚型有更好的疗效。在这方面,利用ER信号传导的治疗干预措施
故障,超过70%的BCAs的驱动因素,在BCa治疗和/或化疗中取得了一定的成功,
预防然而,尽管最初的好处,大多数患者最终复发,由于获得性耐药性,这些
毒品此外,三阴性乳腺癌(TNBC)没有靶向治疗选择,BCa
缺乏ER、人表皮生长因子受体2(HER 2)和孕酮受体(PR)的亚型,
占BCa发病率的20%以上。因此,越来越多的医疗需求未得到满足。
选择性和有效的药物来治疗所有BCa亚型的早期和耐药阶段。
无论ER表达状态如何,BCa活力都依赖于广泛的表观遗传网络。
修饰剂-组蛋白标记写入器、读取器和擦除器。生物信息学和功能分析已经确定
组蛋白赖氨酸脱甲基酶(KDM)的氨基氧化酶和Jumonji家族的特定亚家族,组蛋白
甲基转移酶(HMT)和组蛋白脱乙酰酶(HDAC)在支持ERα信号传导中至关重要
activation.在这些表观遗传修饰因子中,KDM 1、KDM 3A、KDM 5A、KDM 5 B和KDM 6A是最重要的表观遗传修饰因子。
连接到ERα信号传导中,并且共同对BCa细胞活力至关重要。此外,研究表明,
如KDM 6A在其他ER非依赖性表观遗传重编程中也维持TNBC。不同于ERα
KDM的药理学抑制尚未得到临床验证。虽然抑制KDM 3A,
KDM 5A、KDM 5 B和KDM 6A在体内外均可引起BCa细胞生长停滞,但已有先例
用于在通过选择性缺失旁系成员产生的肿瘤模型中KDM旁系同源物之间进行补偿。
本研究假设,与BCa病因学有关的KDM旁系同源物的集体抑制将使BCa的表达减弱。
KDM旁系同源物之间的补偿可能发生在旁系选择性抑制中,导致
新的选择性和有效的药物来治疗BCa,而不管细胞ER表达状态如何。拟定研究
就是为了验证这个假设具体目标是:1)开发具有良好生物活性的Def基KDM抑制剂,
毒理学和药代动力学(PK)特性。2)表征细胞内靶向之间的相关性
作用(药效学)和全细胞抗增殖活性。3)研究电极导线的体内有效性
化合物在五种BCa鼠模型中的作用。
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 }}
Adegboyega Oyelere其他文献
Adegboyega Oyelere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('Adegboyega Oyelere', 18)}}的其他基金
Reposition and Optimization of Deferiprone for Breast Cancer Therapy
去铁酮在乳腺癌治疗中的重新定位和优化
- 批准号:
10576342 - 财政年份:2021
- 资助金额:
$ 50.54万 - 项目类别:
Reposition and Optimization of Deferiprone for Breast Cancer Therapy
去铁酮在乳腺癌治疗中的重新定位和优化
- 批准号:
10361488 - 财政年份:2021
- 资助金额:
$ 50.54万 - 项目类别:
Histone Deacetylase Inhibitors Equipped with Estrogen Receptor Modulation Activit
具有雌激素受体调节活性的组蛋白脱乙酰酶抑制剂
- 批准号:
8683414 - 财政年份:2014
- 资助金额:
$ 50.54万 - 项目类别:
Nonpeptide macrocyclic histone deacetylase (HDAC) inhibitors for targeted lung ca
用于靶向肺癌的非肽大环组蛋白脱乙酰酶 (HDAC) 抑制剂
- 批准号:
8523012 - 财政年份:2009
- 资助金额:
$ 50.54万 - 项目类别:
Nonpeptide macrocyclic histone deacetylase (HDAC) inhibitors for targeted lung ca
用于靶向肺癌的非肽大环组蛋白脱乙酰酶 (HDAC) 抑制剂
- 批准号:
8112699 - 财政年份:2009
- 资助金额:
$ 50.54万 - 项目类别:
Nonpeptide macrocyclic histone deacetylase (HDAC) inhibitors for targeted lung ca
用于靶向肺癌的非肽大环组蛋白脱乙酰酶 (HDAC) 抑制剂
- 批准号:
7937038 - 财政年份:2009
- 资助金额:
$ 50.54万 - 项目类别:
Nonpeptide macrocyclic histone deacetylase (HDAC) inhibitors for targeted lung ca
用于靶向肺癌的非肽大环组蛋白脱乙酰酶 (HDAC) 抑制剂
- 批准号:
8298481 - 财政年份:2009
- 资助金额:
$ 50.54万 - 项目类别:
Nonpeptide macrocyclic histone deacetylase (HDAC) inhibitors for targeted lung ca
用于靶向肺癌的非肽大环组蛋白脱乙酰酶 (HDAC) 抑制剂
- 批准号:
7785028 - 财政年份:2009
- 资助金额:
$ 50.54万 - 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
Milk fat globule-EGF factor 8 and hepatocyte apoptosis-induced liver wound healing response
乳脂肪球-EGF因子8与肝细胞凋亡诱导的肝脏创面愈合反应
- 批准号:
10585802 - 财政年份:2023
- 资助金额:
$ 50.54万 - 项目类别:
Development of an apoptosis biosensor for monitoring of breast cancer
开发用于监测乳腺癌的细胞凋亡生物传感器
- 批准号:
10719415 - 财政年份:2023
- 资助金额:
$ 50.54万 - 项目类别:
Interrogating the Fgl2-FcγRIIB axis on CD8+ T cells: A novel mechanism mediating apoptosis of tumor-specific memory CD8+ T cells
询问 CD8 T 细胞上的 Fgl2-FcγRIIB 轴:介导肿瘤特异性记忆 CD8 T 细胞凋亡的新机制
- 批准号:
10605856 - 财政年份:2023
- 资助金额:
$ 50.54万 - 项目类别:
Novel targeted therapy for FGFR inhibitor-resistant urothelial cancer and apoptosis based therapy for urothelial cancer
FGFR抑制剂耐药性尿路上皮癌的新型靶向治疗和基于细胞凋亡的尿路上皮癌治疗
- 批准号:
23K08773 - 财政年份:2023
- 资助金额:
$ 50.54万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Mechanistic analysis of apoptosis induction by HDAC inhibitors in head and neck cancer
HDAC抑制剂诱导头颈癌凋亡的机制分析
- 批准号:
23K15866 - 财政年份:2023
- 资助金额:
$ 50.54万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
Interrogating the Fgl2-FcgRIIB axis: A novel mechanism mediating apoptosis of tumor-specific memory CD8+ T cells
探究 Fgl2-FcgRIIB 轴:介导肿瘤特异性记忆 CD8 T 细胞凋亡的新机制
- 批准号:
10743485 - 财政年份:2023
- 资助金额:
$ 50.54万 - 项目类别:
Investigating the role of apoptosis-resistance and the tumor environment on development and maintenance of sacrococcygeal teratomas
研究细胞凋亡抗性和肿瘤环境对骶尾部畸胎瘤发生和维持的作用
- 批准号:
10749797 - 财政年份:2023
- 资助金额:
$ 50.54万 - 项目类别:
The effects of glucose on immune cell apoptosis and mitochondrial membrane potential and the analysis of its mechanism by which glucose might modulate the immune functions.
葡萄糖对免疫细胞凋亡和线粒体膜电位的影响及其调节免疫功能的机制分析。
- 批准号:
22K09076 - 财政年份:2022
- 资助金额:
$ 50.54万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
XAF1 IN P53 SIGNALING, APOPTOSIS AND TUMOR SUPPRESSION
P53 信号传导、细胞凋亡和肿瘤抑制中的 XAF1
- 批准号:
10583516 - 财政年份:2022
- 资助金额:
$ 50.54万 - 项目类别:
Role of Thioredoxin system in regulation of autophagy-apoptosis cross talk in neurons: Uncovering Novel Molecular Interactions.
硫氧还蛋白系统在神经元自噬-凋亡串扰调节中的作用:揭示新的分子相互作用。
- 批准号:
RGPIN-2019-05371 - 财政年份:2022
- 资助金额:
$ 50.54万 - 项目类别:
Discovery Grants Program - Individual