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Probes, Inhibitors, and PROTACs (PIP) Core

Probes, Inhibitors, and PROTACs (PIP) Core
探针、抑制剂和 PROTAC (PIP) 核心
批准号:
10714240
负责人:
Amarnath Natarajan
金额:
$18.58万
依托单位国家:
美国
项目类别:
财政年份:
2018
资助国家:
美国
项目状态:
未结题
起止时间:
2018-03-16 至 2028-06-30
关键词:
AddressAdrenal GlandsAlkynesAllelesAmino Acid SequenceBindingBinding SitesBiologicalBiologyBiotinBiotinylationCDK4 geneCDK5 geneCellsCenters of Research ExcellenceChemicalsChemistryColorectal CancerCommunitiesComplexCoupledDNA SequenceDNA lesionDataDevelopmentDrug TargetingDrug resistanceEnvironmentEvaluationExcisionExperimental GeneticsFDA approvedFaculty RecruitmentFundingFutureGeneticGenetic CodeGlycolysisGrantKineticsLegal patentLibrariesLysineMapsMass Spectrum AnalysisMethodsMissionModificationMolecularMolecular TargetMutateNebraskaNeurologicNucleic AcidsOrganoidsPathway AnalysisPhosphorylationPhosphotransferasesPost-Translational Protein ProcessingProtacProtein AnalysisProteinsProteomeProteomicsPublicationsRNA SequencesRecombinant ProteinsRegulationResearchResearch PersonnelResearch Project GrantsRoleScientistServicesSignal PathwaySignal TransductionSignaling MoleculeSiteStructureStructure-Activity RelationshipSystemT-LymphocyteTechnologyTherapeuticTimeTissuesUbiquitinUniversitiesValidationanalogassay developmentcancer biomarkerschemical geneticschemical synthesisdesigndifferential expressiondrug discoveryexperienceexperimental studyfunctional groupin vivoinhibitorinstrumentationinterestlead optimizationmedullary thyroid carcinomamembermulticatalytic endopeptidase complexneuroendocrine cancerneuropsychiatrynovelp53-binding protein 1pre-clinicalprogramsprotein degradationprotein functionprotein protein interactionrecruitresistance mechanismscaffoldscale upsmall moleculesmall molecule librariesspatiotemporaltherapeutic developmenttherapeutic targettooltreatment responseubiquitin-protein ligase

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中文摘要
翻译
项目概述:探针,抑制剂和PROTACs (PIP)核心
英文摘要
Project Summary: Probes, Inhibitors, and PROTACs (PIP) Core The overarching mission of the PIP Core is to use sophisticated chemistry and mass spectrometry for development of small molecules that facilitate molecular target discovery and development. Genetic methods are routinely used to identify, develop, and validate molecular targets. These methods rely on altering the DNA or RNA sequences of the protein target. However, drug discovery relies on manipulating the function of the corresponding proteins using small molecules. Often the results obtained through these complementary strategies do not correlate.1 The incongruence associated with the results from these orthogonal approaches can be attributed to the complex biology that is dependent on multiple functions i.e., enzymatic and scaffolding, associated with the protein target. Modulating protein levels by altering the nucleic acids eliminates all the target protein functions. However small molecule modulators can be tuned to induce either domain specific effects (reversible or irreversible) or removal of the entire protein (PROTAC) with exquisite temporal control. These could be tagged with photoactivatable or fluorescent molecules, or biotin to enable target identification and validation, study mechanism of action, or characterize the associated interactome. In addition to the design and synthesis of above types of small molecules, the PIP Core will also provide scale up services (mg to g) for additional experiments such as in vivo validation of targets and hit-to-lead optimization studies to generate structure activity relationship (SAR) data. Mass spectrometry will be used to characterize the impact of these compounds on the proteome through quantitative analysis of proteins and posttranslational or chemical modifications to validate mechanism of action and compensatory features that may contribute to drug resistance. The Core will be led by Drs. Natarajan and Woods, who will bring complementary expertise to the PIP Core. Dr. Natarajan has extensive expertise in developing probes, inhibitors, and PROTACs, using cutting edge chemistry methods. Dr. Woods has extensive experience using mass spectrometry as a platform for delineating protein- protein interactions, posttranslational modifications, and multivariate biomarkers of cancer response to therapy. PIP Core services will be extensively utilized by CMTDD Research Project Leaders (RPLs), CMTDD members and University researchers at large.
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