A transformative drug discovery platform for allosteric kinase inhibitors
变构激酶抑制剂的变革性药物发现平台
基本信息
- 批准号:10595089
- 负责人:
- 金额:$ 57.17万
- 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:AccelerationAdoptionAffinityBasic ScienceBindingBiochemicalBiological AssayBiophysicsBiosensorCancer PatientCancer cell lineChemicalsClassificationClinicalComplexCouplesDetectionDevelopmentDiseaseDissociationExonsFDA approvedFluorescenceFluorescence Resonance Energy TransferIndustrializationKnowledgeLibrariesLigandsMET geneMalignant NeoplasmsMalignant neoplasm of lungMediatingMinnesotaMissionMolecular ConformationMonitorMovementMutationOncologyOncoproteinsPatientsPhosphotransferasesProto-Oncogene Proteins c-mycReaderReceptor Protein-Tyrosine KinasesRegulatory ElementResearchResistanceResistance developmentSiteTechnologyTestingTherapeuticTranslatingUbiquitinationUniversitiesValidationc-myc Genescrizotinibdrug developmentdrug discoveryfield studyfollow-uphigh throughput screeningindustry partnerinhibitorinnovationinstrumentationkinase inhibitornanosecondnext generationnovelnovel strategiesnovel therapeutic interventionnovel therapeuticsphotonicspreventprogramsresistance mutationscaffoldsensorsensor technologysmall moleculesuccesstechnology developmenttherapeutic targettreatment strategytumortumorigenesis
项目摘要
Project Summary
The University of Minnesota (UMN) and Photonic Pharma (PP) a Minnesota-based drug discovery start-up, have
partnered to optimize, field-test, and deploy at industrial scale, an innovative new approach to developing
allosteric kinase inhibitors (AKI). These molecules have high potential as novel cancer therapeutics that
circumvent clinical resistance to conventional orthosteric kinase inhibitors (OKI). We have developed high-
throughput screening (HTS) technology based on nanosecond fluorescence lifetime (FLT) detection of Förster
resonance energy transfer (FRET), that tracks ligand-driven kinase allostery with angstrom precision by
monitoring structural changes of the activation loop, the key regulatory element in all kinases. This is the first
HTS-amenable technology that accurately resolves allosteric effects of kinase inhibitors, relying on high-quality
nanosecond FLT readouts unavailable from conventional fluorescence plate readers (PR). PP have developed
a proprietary HTS platform that uses FRET biosensors and a state-of-the-art FLT-PR to detect structural
readouts in <2 min for 384-well and <5 min for 1536-well plates. By partnering with PP, we will transform our
kinase FRET sensor technology into a broadly applicable drug-discovery platform for identifying AKIs.
We propose drug-discovery programs on two different targets to demonstrate broad utility and accelerate large-
scale adoption of our technology for drug development. In AIM 1, we identify Aurora A inhibitors that
downregulate the undruggable c-Myc oncoprotein by inhibiting the scaffolding interaction of Aurora A with c-
Myc. These molecules would represent a novel treatment strategy for the large number of cancer patients with
c-Myc-driven tumors. In AIM 2, we identify allosteric inhibitors of the c-MET receptor tyrosine kinase as a novel
therapeutic strategy for patients with c-MET-driven lung cancer. These patients invariably develop resistance to
current MET inhibitors through acquired mutations in the ATP site, and allosteric inhibitors that bind outside the
ATP-site would circumvent this mode of resistance, filling an unmet clinical need. This UMN-PP partnership
translates decades of biophysics research by two world-leading experts – Levinson and Thomas – toward drug-
discovery by resolving ligand-driven allostery in kinases. This is enabled by the FLT-PR instrumentation and
know-how required to implement nanosecond FLT detection in assays that resolve allosteric inhibitors in true
HTS mode. This overcomes key drawbacks of conventional kinase inhibitor screens, which detect kinase
inhibition or binding without regard to allosteric mechanism. The platform is broadly applicable, as almost all
kinases undergo the large-scale allosteric structural changes our technology detects. Success of this
project will catalyze adoption of this technology targeting a wide range of biomedically important kinases, as
highlighted by Photonic Pharma’s successful partnership with Bristol-Myers Squibb on drug discovery for other
high-priority therapeutic targets.
项目总结
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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Nicholas Mark Levinson其他文献
Nicholas Mark Levinson的其他文献
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{{ truncateString('Nicholas Mark Levinson', 18)}}的其他基金
Targeting allosteric scaffolding functions of Aurora kinase A in cancer
靶向癌症中极光激酶 A 的变构支架功能
- 批准号:
10373096 - 财政年份:2021
- 资助金额:
$ 57.17万 - 项目类别:
A transformative drug discovery platform for allosteric kinase inhibitors
变构激酶抑制剂的变革性药物发现平台
- 批准号:
10097782 - 财政年份:2021
- 资助金额:
$ 57.17万 - 项目类别:
Targeting allosteric scaffolding functions of Aurora kinase A in cancer
靶向癌症中极光激酶 A 的变构支架功能
- 批准号:
10210065 - 财政年份:2021
- 资助金额:
$ 57.17万 - 项目类别:
Targeting allosteric scaffolding functions of Aurora kinase A in cancer
靶向癌症中极光激酶 A 的变构支架功能
- 批准号:
10593935 - 财政年份:2021
- 资助金额:
$ 57.17万 - 项目类别:
A transformative drug discovery platform for allosteric kinase inhibitors
变构激酶抑制剂的变革性药物发现平台
- 批准号:
10360449 - 财政年份:2021
- 资助金额:
$ 57.17万 - 项目类别:
Time-resolved FRET-based allostery sensors for any protein kinase drug target
适用于任何蛋白激酶药物靶标的时间分辨 FRET 变构传感器
- 批准号:
9887709 - 财政年份:2020
- 资助金额:
$ 57.17万 - 项目类别:
Time-resolved FRET-based allostery sensors for any protein kinase drug target
适用于任何蛋白激酶药物靶标的时间分辨 FRET 变构传感器
- 批准号:
10348717 - 财政年份:2020
- 资助金额:
$ 57.17万 - 项目类别:
Decoding the dynamic mechanism of allosteric activation in the cyclin-dependent kinase Cdk2
解读细胞周期蛋白依赖性激酶 Cdk2 变构激活的动态机制
- 批准号:
10321568 - 财政年份:2018
- 资助金额:
$ 57.17万 - 项目类别:
Kinome-Wide Spectroscopic Study of Drug Binding Site Electrostatics
药物结合位点静电的全激酶组光谱研究
- 批准号:
8351780 - 财政年份:2012
- 资助金额:
$ 57.17万 - 项目类别:
Kinome-Wide Spectroscopic Study of Drug Binding Site Electrostatics
药物结合位点静电的全激酶组光谱研究
- 批准号:
8973668 - 财政年份:2012
- 资助金额:
$ 57.17万 - 项目类别:
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