Photoaffinity labeling probes for development of novel isoform selective HDAC inh
用于开发新型亚型选择性 HDAC inh 的光亲和标记探针
基本信息
- 批准号:8067976
- 负责人:
- 金额:$ 30.83万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2008
- 资助国家:美国
- 起止时间:2008-07-01 至 2013-04-30
- 项目状态:已结题
- 来源:
- 关键词:AbbreviationsAddressAffectAzidesBindingBiological TestingBiologyBiotinCell DeathChemicalsClinical TrialsComplexComputer AssistedDevelopmentDiseaseDockingDrug DesignEnzymesFDA approvedFingerprintGene Expression RegulationGoalsHDAC1 geneHDAC7 histone deacetylaseHealthHela CellsHistone DeacetylaseHistone Deacetylase InhibitorHomology ModelingImageIndividualLabelLifeLigand BindingLigandsMalignant NeoplasmsMapsMass Spectrum AnalysisMethodsModificationNaturePharmaceutical ChemistryPhotoaffinity LabelsProblem SolvingProtein IsoformsProteinsProteomicsRecombinantsResearchResolutionSeriesSiteStructureStudy modelsSurfaceTestingTherapeuticToxic effectTranscription factor genesTreatment EfficacyZincanti-cancer therapeuticbasecancer therapycell growthcytotoxicitydesigndrug discoveryhistone acetyltransferasehuman HDAC1 proteinhuman HDAC11 proteinimprovedinhibitor/antagonistinnovationknowledge of resultsmolecular dynamicsmultidisciplinaryneoplastic cellnovelnovel strategiesresearch studysmall moleculesuccessthree dimensional structure
项目摘要
DESCRIPTION (provided by applicant): This proposal is intended to charter new directions for design of more selective and more active histone deacetylase (HDAC) inhibitors by mapping the binding "fingerprints" of the HDAC ligands in the different HDAC isoforms using small molecule photoaffinity probes. Since many cancers are associated with aberrant transcriptional activity, and the HDACs can affect transcription factors and gene regulation, these enzymes have been identified as attractive targets for cancer therapy. Indeed, chemical inhibitors of HDACs have been shown to inhibit tumor cell growth and induce differentiation and cell death. At least one non-selective HDAC inhibitor was approved by FDA for cancer and several non-selective HDAC inhibitors are in clinical trials. Multiple studies have shown that therapeutics selective for one or a limited number of specific HDAC isoforms may improve overall efficacy and lower toxicity of these compounds. While some rather limited degree of isoform selectivity has been shown by a few compounds, the problem of identifying selective inhibitors is far from solved. Recent success in the elucidation of the crystal structure of HDAC7, 8 and homologous HDAC proteins has opened a possibility for structure-based drug design. Despite the progress, both ligand-based and structure-based approaches are limited in their applicability to design of isoform selective HDAC inhibitors either because only few isoform selective inhibitors are available as a starting point for ligand based drug design or because high resolution three-dimensional structures are available only for 2 out of 11 class I and II HDAC isoforms. It is also poorly understood how the binding modes of those portions of the HDAC ligands that bind on the surface of the HDAC protein affect the activity of HDAC inhibitors. Clearly, a new approach to this problem is needed. We hypothesize that it will be possible to map the binding modes available to the ligands in different HDAC isoforms by small molecule photoaffinity probes (PAP) and use the resulting knowledge to design isoform selective HDAC inhibitors as potential therapeutics for cancer. Our specific aims in this proposal are as follow: Aim 1: Design and synthesize at least three series of photoaffinity probes (PAPs) consisting of (1) an HDAC ligand, (2) an aromatic azide group for photoaffinity labeling (PAL) of the protein residues directly involved in the binding of the ligand, and (3) an aliphatic azide (a imaging tag attachment group - imTAG) for attaching a fluorescent or a biotin tag. Aim 2: Evaluate the ligands containing either PAL or PAL+imTAG or both groups in photoaffinity labeling experiments with available recombinant purified class I and class II HDACs and determine the modification sites on the proteins using mass-spectrometry proteomics methods. Match the proteomics results with the modeling studies and refine later to better reproduce the experimental findings. Aim 3. Evaluate the cytotoxicity, selectivity, and binding "fingerprints" of the most potent photoaffinity probes in live Hela cells. Aim 4. Incorporate the findings of Aims 1-3 in the structure-based drug design and perform several rounds of CADD, medicinal chemistry, and biological tests to improve the activity and selectivity of the HDAC ligands. PUBLIC HEALTH RELEVANCE: This proposal is intended to charter new directions for design of more selective and more active histone deacetylase (HDAC) inhibitors by mapping the binding "fingerprints" of the HDAC ligands in the different HDAC isoforms using small molecule photoaffinity probes. The ultimate goal of this proposal is to design HDAC inhibitors suitable as HDAC based therapeutics for cancer and other HDAC relevant diseases and conditions.
描述(由申请人提供):该提案旨在通过使用小型分子光化的小分子光探针在不同HDAC同工型中映射不同HDAC同工型的HDAC配体的结合“指纹”,以章程设计新的方向,以设计更具选择性和更活跃的组蛋白脱乙酰基酶(HDAC)抑制剂。由于许多癌症与异常转录活性有关,并且HDACS会影响转录因子和基因调节,因此这些酶已被确定为癌症治疗的有吸引力的靶标。实际上,HDAC的化学抑制剂已被证明可以抑制肿瘤细胞的生长并诱导分化和细胞死亡。 FDA批准了至少一种非选择性的HDAC抑制剂,用于癌症,几种非选择性的HDAC抑制剂正在临床试验中。多项研究表明,一种或有限数量的特定HDAC同工型的治疗方法可以提高整体功效和降低这些化合物的毒性。尽管一些化合物已经表明了一些相当有限的同工型选择性,但识别选择性抑制剂的问题尚未解决。 HDAC7,8和同源HDAC蛋白的晶体结构的最新成功为基于结构的药物设计开辟了可能性。尽管取得了进展,但基于配体和基于结构的方法的适用性在设计同工型选择性HDAC抑制剂上的适用性受到限制,因为仅少量同工型选择性抑制剂可作为基于配体的药物设计的起点,或者是因为高分辨率的三维结构仅可用,只能在11类I和II类HDAC类中使用2次。还鲜为人知的是,在HDAC蛋白表面结合的HDAC配体的这些部分的结合模式如何影响HDAC抑制剂的活性。显然,需要一种新的方法来解决此问题。我们假设可以通过小分子光接触探针(PAP)绘制不同HDAC同工型中配体可用的结合模式,并使用所得的知识来设计同工型选择性HDAC抑制剂作为癌症的潜在疗法。该提案中我们的具体目的如下:目标1:设计和合成至少三个系列光接触探针(PAPS),包括(1)HDAC配体,(2)芳香族叠氮化物的芳香族叠氮化物(PAL)蛋白质残基的光接触(PAL),直接与配体的粘合物和(3)Anip Anip a Zide Anip Anip azide(3)的蛋白质残基相连(3)荧光或生物素标签。 AIM 2:使用可用的重组纯化的I类和II类HDAC进行光性标记实验中包含PAL或PAL+IMTAG的配体,并使用质谱蛋白质组蛋白质组学方法确定蛋白质上的修饰位点。将蛋白质组学的结果与建模研究相匹配,并以后进行完善,以更好地再现实验发现。目标3。评估活HeLa细胞中最有效的光性探针的细胞毒性,选择性和结合“指纹”。 AIM 4。将目标1-3的发现纳入基于结构的药物设计中,并进行几轮CADD,药物化学和生物学测试,以提高HDAC配体的活性和选择性。 公共卫生相关性:该提案旨在通过使用小型分子光吸气探针在不同HDAC同工型中绘制HDAC配体中HDAC配体的结合“指纹”来设计新的方向,以设计更具选择性和更活跃的组蛋白脱乙酰基酶(HDAC)抑制剂。该提案的最终目标是设计适合基于HDAC的癌症和其他HDAC相关疾病和疾病的HDAC抑制剂。
项目成果
期刊论文数量(9)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Scaffold dependent histone deacetylase (HDAC) inhibitor induced re-equilibration of the subcellular localization and post-translational modification state of class I HDACs.
支架依赖性组蛋白脱乙酰酶 (HDAC) 抑制剂诱导 I 类 HDAC 的亚细胞定位和翻译后修饰状态的重新平衡。
- DOI:10.1371/journal.pone.0186620
- 发表时间:2017
- 期刊:
- 影响因子:3.7
- 作者:Hanigan,ThomasW;Taha,TahaY;Aboukhatwa,ShaimaaM;Frasor,Jonna;Petukhov,PavelA
- 通讯作者:Petukhov,PavelA
Design, synthesis, modeling, biological evaluation and photoaffinity labeling studies of novel series of photoreactive benzamide probes for histone deacetylase 2.
用于组蛋白脱乙酰酶 2 的新型光反应性苯甲酰胺探针系列的设计、合成、建模、生物学评估和光亲和标记研究。
- DOI:10.1016/j.bmcl.2012.06.017
- 发表时间:2012
- 期刊:
- 影响因子:2.7
- 作者:Vaidya,AdityaSudheer;Karumudi,Bhargava;Mendonca,Emma;Madriaga,Antonett;Abdelkarim,Hazem;vanBreemen,RichardB;Petukhov,PavelA
- 通讯作者:Petukhov,PavelA
Parameterization of aromatic azido groups: application as photoaffinity probes in molecular dynamics studies.
- DOI:10.1007/s00894-009-0488-z
- 发表时间:2009-11
- 期刊:
- 影响因子:2.2
- 作者:Pieffet, Gilles;Petukhov, Pavel A.
- 通讯作者:Petukhov, Pavel A.
Design, Synthesis, and Biological Evaluation of Tetrahydroisoquinoline-Based Histone Deacetylase 8 Selective Inhibitors.
- DOI:10.1021/acsmedchemlett.7b00126
- 发表时间:2017-08
- 期刊:
- 影响因子:4.2
- 作者:T. Y. Taha;Shaimaa M. Aboukhatwa;Rachel C Knopp;N. Ikegaki;Hazem Abdelkarim;Jayaprakash Neerasa;Yunlong Lu;Raghupathi Neelarapu;T. Hanigan;G. Thatcher;P. Petukhov
- 通讯作者:T. Y. Taha;Shaimaa M. Aboukhatwa;Rachel C Knopp;N. Ikegaki;Hazem Abdelkarim;Jayaprakash Neerasa;Yunlong Lu;Raghupathi Neelarapu;T. Hanigan;G. Thatcher;P. Petukhov
A One-Pot Selective Synthesis of N-Boc Protected Secondary Amines: Tandem Direct Reductive Amination/N-Boc Protection.
N-Boc 保护仲胺的一锅选择性合成:串联直接还原胺化/N-Boc 保护。
- DOI:10.1016/j.tet.2012.06.055
- 发表时间:2012
- 期刊:
- 影响因子:2.1
- 作者:Neelarapu,Raghupathi;Petukhov,PavelA
- 通讯作者:Petukhov,PavelA
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Pavel A Petukhov其他文献
Pavel A Petukhov的其他文献
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{{ truncateString('Pavel A Petukhov', 18)}}的其他基金
Identification of the target of meclonazepam in schistosome worms
甲氯硝西泮在血吸虫中作用靶点的鉴定
- 批准号:
10218461 - 财政年份:2021
- 资助金额:
$ 30.83万 - 项目类别:
Identification of the target of meclonazepam in schistosome worms
甲氯硝西泮在血吸虫中作用靶点的鉴定
- 批准号:
10357874 - 财政年份:2021
- 资助金额:
$ 30.83万 - 项目类别:
Identification of preclinical drug candidates for the treatment of schistosomiasis
治疗血吸虫病的临床前候选药物的鉴定
- 批准号:
9813829 - 财政年份:2016
- 资助金额:
$ 30.83万 - 项目类别:
Small Molecule Inhibitors of Malate Synthase against M. Tuberculosis
抗结核分枝杆菌的苹果酸合酶小分子抑制剂
- 批准号:
7706254 - 财政年份:2009
- 资助金额:
$ 30.83万 - 项目类别:
Small Molecule Inhibitors of Malate Synthase against M. Tuberculosis
抗结核分枝杆菌的苹果酸合酶小分子抑制剂
- 批准号:
7897873 - 财政年份:2009
- 资助金额:
$ 30.83万 - 项目类别:
Photoaffinity labeling probes for development of novel isoform selective HDAC inh
用于开发新型亚型选择性 HDAC inh 的光亲和标记探针
- 批准号:
7525598 - 财政年份:2008
- 资助金额:
$ 30.83万 - 项目类别:
Photoaffinity labeling probes for development of novel isoform selective HDAC inh
用于开发新型亚型选择性 HDAC inh 的光亲和标记探针
- 批准号:
7841892 - 财政年份:2008
- 资助金额:
$ 30.83万 - 项目类别:
Photoaffinity labeling probes for development of novel isoform selective HDAC inh
用于开发新型亚型选择性 HDAC inh 的光亲和标记探针
- 批准号:
7648175 - 财政年份:2008
- 资助金额:
$ 30.83万 - 项目类别:
Small molecule inhibitors pantothenate synthesis against M. tuberculosis
针对结核分枝杆菌的小分子泛酸合成抑制剂
- 批准号:
7243999 - 财政年份:2006
- 资助金额:
$ 30.83万 - 项目类别:
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- 批准号:
7021009 - 财政年份:2006
- 资助金额:
$ 30.83万 - 项目类别:
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