Discovery of small molecule inhibitors of GalNAc-type O-linked glycosylation
GalNAc 型 O-连接糖基化小分子抑制剂的发现
基本信息
- 批准号:9763582
- 负责人:
- 金额:$ 25.43万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-09-01 至 2021-08-31
- 项目状态:已结题
- 来源:
- 关键词:AcetylgalactosamineAffinityAnabolismAsthmaBehaviorBindingBiochemicalBiological AssayBiological ProcessBiophysicsCell-Cell AdhesionCellsChemicalsCollaborationsCollectionComplexCore FacilityDataDevelopmentDiseaseDoseEnvironmentEnzymesEpithelial CellsEventFamilyFibroblast Growth FactorGenetic DiseasesGenetic TranscriptionGlycoconjugatesGlycolipidsGlycoproteinsGrantHuman GeneticsIn VitroIntegrinsKineticsLeadLibrariesLinkLung diseasesMalignant NeoplasmsMalignant neoplasm of lungMalignant neoplasm of pancreasMammalian CellMass Spectrum AnalysisMeasuresModificationMolecularMonitorMucinsMucous body substanceN-AcetylgalactosaminyltransferasesNatural ProductsNeoplasm MetastasisNon-Small-Cell Lung CarcinomaOrganismOutcomeOxygenPathologyPeptidesPharmaceutical PreparationsPharmacologyPlayPolysaccharidesProcessProductionProtein BiosynthesisProtein GlycosylationProteinsReactionResearchRoleSerineSignal TransductionStructureStructure-Activity RelationshipTestingThreonineUniversitiesZavescabasecancer celldrug discoveryenzyme substrateexperimental studyextracellularglycosylationglycosyltransferasehigh throughput screeningin vitro activityinhibitor/antagonistinnovationnovel therapeutic interventionnovel therapeuticspharmacophorepolypeptidepre-clinicalrespiratorysmall moleculesmall molecule inhibitorsugar nucleotidetherapy developmenttooltumor progression
项目摘要
Many extracellular and secreted proteins are post-translationally modified with glycans,
including N-acetylgalactosamine (GalNAc)-type O-linked glycans. This common form of protein
glycosylation is initiated by addition of GalNAc to oxygen atoms of serine or threonine residues.
GalNAc-type O-linked glycosylation plays functional roles in diverse biological processes
including mucin assembly, developmental signaling, human genetic disorders, cell-cell adhesion
events, and cancer progression. Despite playing essential roles, mechanistic understanding of
the functions of GalNAc-type O-linked glycosylation is incomplete, due in part to the inadequacy
of tools available to probe and control this modification. To meet this challenge, we will carry
out a high-throughput screening (HTS) campaign to discover small molecules that inhibit the
polypeptide GalNAc-transferase (ppGalNAcT) family of enzymes, responsible for adding GalNAc
residues to proteins to initiate GalNAc-type O-linked glycan biosynthesis. Our primary HTS
assay is a mass spectrometry-based assay using purified ppGalNAcT1 enzyme and a mucin-
derived peptide as a glycosylation substrate. We will screen the 330,000-compound collection
from the UT Southwestern HTS core facility, including commercial compounds and natural
product fractions. Compounds that show potent and dose-dependent inhibition of ppGalNAcTs
in vitro will be evaluated for ppGalNAcT inhibition in cells. We will also use a plate-based assay
to test whether hit molecules inhibit mucin secretion from respiratory epithelial cells, a process
that depends on GalNAc-type O-linked glycans. Candidate inhibitors that display cell-based
activity will be further analyzed by a cascade of assays aimed at testing the mechanism of action
and selectivity of inhibition. Structure-activity relationship (SAR) analysis will be performed on
top compounds. A handful of high-performing inhibitors will be subjected to a full molecular
characterization including analysis of kinetic mechanism, profiling of induced transcriptional
and glycosylation changes, measuring affinity of ppGalNAcT binding, structural characterization
of the inhibitor-ppGalNAcT complex, and a proof-of-concept experiment testing effects on the
migratory behavior of lung cancer cells. At the end of the granting period, we aim to identify one
or more pharmacophores that provide potent and selective inhibition of the ppGalNAcT family
in vitro and in cells. In addition to their utility as chemical probes for academic research, these
compounds may have the potential to serve as lead molecules for new therapeutic approaches to
treat cancers, such as pancreatic cancer and non-small cell lung cancer (NSCLC), and
respiratory disease, including asthma, that are characterized by mucus overproduction.
许多细胞外蛋白和分泌蛋白在翻译后被聚糖修饰,
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)
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Jennifer J Kohler其他文献
Transcriptional Control of Gene Expression By O-Glcnacylation during Erythropoiesis
- DOI:
10.1182/blood-2024-201756 - 发表时间:
2024-11-05 - 期刊:
- 影响因子:
- 作者:
Kenneth R Peterson;Matthew P Parker;Aspin Denson;Will Brautman;Nick Lowe;Halyna Fedosyuk;Lesya V Novikova;Jeffrey A Thompson;Jennifer J Kohler;Chad Slawson - 通讯作者:
Chad Slawson
A shift for the O-GlcNAc paradigm
O-GlcNAc 范式的转变
- DOI:
10.1038/nchembio.429 - 发表时间:
2010-09-01 - 期刊:
- 影响因子:13.700
- 作者:
Jennifer J Kohler - 通讯作者:
Jennifer J Kohler
Jennifer J Kohler的其他文献
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{{ truncateString('Jennifer J Kohler', 18)}}的其他基金
Function and regulation of epithelial glycosylation
上皮糖基化的功能和调节
- 批准号:
10621189 - 财政年份:2022
- 资助金额:
$ 25.43万 - 项目类别:
DISSECTING AND TARGETING THE ROLE OF GALNT14 IN HIGH-RISK OSTEOSARCOMA
剖析和瞄准 GALNT14 在高风险骨肉瘤中的作用
- 批准号:
10761850 - 财政年份:2022
- 资助金额:
$ 25.43万 - 项目类别:
DISSECTING AND TARGETING THE ROLE OF GALNT14 IN HIGH-RISK OSTEOSARCOMA
剖析和瞄准 GALNT14 在高风险骨肉瘤中的作用
- 批准号:
10363579 - 财政年份:2022
- 资助金额:
$ 25.43万 - 项目类别:
Function and regulation of epithelial glycosylation
上皮糖基化的功能和调节
- 批准号:
10414154 - 财政年份:2022
- 资助金额:
$ 25.43万 - 项目类别:
Photocrosslinking probes to discover glycan-dependent interactions
光交联探针发现聚糖依赖性相互作用
- 批准号:
9166533 - 财政年份:2016
- 资助金额:
$ 25.43万 - 项目类别:
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