High Throughput Screen for Discovery of N-Acetyltransferase 8 Like (NAT8L) Inhibitors
用于发现 N-乙酰转移酶 8 样 (NAT8L) 抑制剂的高通量筛选
基本信息
- 批准号:10704342
- 负责人:
- 金额:$ 40.93万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-12-15 至 2024-11-30
- 项目状态:已结题
- 来源:
- 关键词:ABCB1 geneAcetyl Coenzyme AAcetyltransferaseAddressAnabolismAnimalsAntisense OligonucleotidesAspartateAspartoacylaseBiological AssayBrainBrain EdemaCanavan DiseaseCellsCentral Nervous SystemCerebellumCerebrumCessation of lifeChemicalsClinicalCognitive deficitsCollectionDataDemyelinationsDeteriorationDevelopmentDiseaseDoseDrug KineticsEnzymesExhibitsFluorescenceFutureGene DeletionGenesGeneticGoalsHumanIn VitroLeadLibrariesMacrocephalyMetabolicMolecularMolecular BankMusMutationMyelinN-acetylaspartatePatientsPenetrationPermeabilityPharmaceutical ChemistryPharmaceutical PreparationsPre-Clinical ModelPrion DiseasesPropertyProsencephalonRadioactivityResearch PersonnelRoboticsRodent ModelSolubilitySupportive careSymptomsTestingTherapeuticUnited States National Institutes of Healthanalogaqueousassay developmentastrogliosisautosomecarboxylatecarboxylationdrug candidatedrug discoverydrug metabolismenzyme activityhigh throughput screeningin vivoinfancyinhibitorlead optimizationleukodystrophymotor deficitmouse modelmyelinationnervous system disorderneuropathologyneurotransmissionnovelnovel therapeutic interventionpharmacophorepreventprocess optimizationrepositoryresponsesmall moleculesmall molecule inhibitorsmall molecule librariessymptom managementtherapeutic candidatetherapeutic developmenttrendwhite matter
项目摘要
PROJECT SUMMARY
Canavan disease (CD) is rare autosomal recessive leukodystrophy caused by mutations in the
aspartoacylase gene (ASPA), leading to loss of enzyme activity and increased concentrations of the
substrate N-acetylaspartate (NAA) in the brain. Accumulation of brain NAA results in spongiform
degeneration of white matter, aberrant myelination, brain edema, macrocephaly, severe cognitive and motor
deficits and ultimately death. There is no cure, nor is there a standard course of treatment for CD. Treatment
is currently limited to supportive care and symptom management. Genetic deletion of the ASPA gene in mice
has been shown to reproduce many of the CD disease symptoms seen in patients. Important to this proposal,
deletion of the gene encoding for aspartate N-acetyltransferase 8 (NAT8L), the enzyme that catalyzes the
biosynthesis of NAA from aspartate and acetyl CoA, prevented leukodystrophy in a CD mouse model. These
mice showed substantial reduction in NAA levels and no evidence of astroglial vacuolation, astrogliosis, or
demyelination in the cerebellum or forebrain. Similar therapeutic benefits were observed with intracisternal
administration of antisense oligonucleotide to NAT8L. These results strongly suggest that inhibition of NAT8L
would be useful in the treatment of CD. Currently, however, there are no NAT8L inhibitors that are clinically
available; known NAT8L inhibitors have low potency (IC50 values in the μM - mM range) and/or possess
carboxylate moieties that prevent brain penetration. This proposal aims to conduct high throughput screening
(HTS) of a large and diverse 400,000 compound library for small molecule inhibitors of human NAT8L.
Successful identification of tractable hit compounds followed by preliminary structural optimization should
lead to the discovery of promising lead NAT8L inhibitors with potential for future development of therapeutics
for CD. We are poised to seize this opportunity by executing the following three Specific Aims: (Aim 1)
conduct NAT8L HTS and hit confirmation assays; (Aim 2) conduct hit clustering, preliminary SAR, and ADME
profiling; (Aim 3) conduct preliminary lead optimization.
项目总结
项目成果
期刊论文数量(0)
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Barbara Stauch Slusher其他文献
Immunocytochemical localization of the N‐acetyl‐aspartyl‐glutamate (NAAG) hydrolyzing enzyme N‐acetylated α‐linked acidic dipeptidase (NAALADase)
N-乙酰-天冬氨酰-谷氨酸 (NAAG) 水解酶 N-乙酰化 α-连接酸性二肽酶 (NAALADase) 的免疫细胞化学定位
- DOI:
- 发表时间:
1992 - 期刊:
- 影响因子:0
- 作者:
Barbara Stauch Slusher;G. Tsai;Grace Yoo;J. Coyle - 通讯作者:
J. Coyle
Barbara Stauch Slusher的其他文献
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{{ truncateString('Barbara Stauch Slusher', 18)}}的其他基金
High throughput screen for discovery of N-acetyltransferase 8 Like (NAT8L) inhibitors
用于发现 N-乙酰转移酶 8 样 (NAT8L) 抑制剂的高通量筛选
- 批准号:
10319002 - 财政年份:2020
- 资助金额:
$ 40.93万 - 项目类别:
Cell-targeted glutamine antagonists as a novel therapy for lymphoma
细胞靶向谷氨酰胺拮抗剂作为淋巴瘤的新疗法
- 批准号:
10408137 - 财政年份:2018
- 资助金额:
$ 40.93万 - 项目类别:
Regulation of Exosome Secretion as a novel therapeutic approach for Alzheimer's Disease
外泌体分泌调节作为阿尔茨海默病的新型治疗方法
- 批准号:
10424423 - 财政年份:2018
- 资助金额:
$ 40.93万 - 项目类别:
Regulation of Exosome Secretion as a novel therapeutic approach for Alzheimer's Disease
外泌体分泌调节作为阿尔茨海默病的新型治疗方法
- 批准号:
10183123 - 财政年份:2018
- 资助金额:
$ 40.93万 - 项目类别:
Cell-targeted glutamine antagonists as a novel therapy for lymphoma
细胞靶向谷氨酰胺拮抗剂作为淋巴瘤的新疗法
- 批准号:
10197023 - 财政年份:2018
- 资助金额:
$ 40.93万 - 项目类别:
GCPII Inihibitors for the treatment of chemotherapy-induced neuropathy
GCPII 抑制剂用于治疗化疗引起的神经病变
- 批准号:
8296943 - 财政年份:2012
- 资助金额:
$ 40.93万 - 项目类别:
GCPII Inihibitors for the treatment of chemotherapy-induced neuropathy
GCPII 抑制剂用于治疗化疗引起的神经病变
- 批准号:
8468134 - 财政年份:2012
- 资助金额:
$ 40.93万 - 项目类别:
GCPII Inihibitors for the treatment of chemotherapy-induced neuropathy
GCPII 抑制剂用于治疗化疗引起的神经病变
- 批准号:
8839732 - 财政年份:2012
- 资助金额:
$ 40.93万 - 项目类别:
GCPII Inihibitors for the treatment of chemotherapy-induced neuropathy
GCPII 抑制剂用于治疗化疗引起的神经病变
- 批准号:
8658046 - 财政年份:2012
- 资助金额:
$ 40.93万 - 项目类别:
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