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

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.
项目摘要 明尼苏达大学(UMN)和光子制药(PP),明尼苏达州的药物发现初创公司, 合作优化,现场测试,并在工业规模部署,一种创新的新方法,以开发 变构激酶抑制剂(阿基)。这些分子具有作为新型癌症治疗剂的高潜力, 避免对常规正构激酶抑制剂(OKI)的临床耐药性。我们已经开发出了高- 基于Förster的纳秒荧光寿命(FLT)检测的通量筛选(HTS)技术 共振能量转移(FRET),通过以下方式以埃精度跟踪配体驱动的激酶变构: 监测激活环的结构变化,激活环是所有激酶的关键调控元件。这是第一 HTS兼容技术,准确解决激酶抑制剂的变构效应,依靠高质量的 纳秒FLT读数无法从传统的荧光板阅读器(PR)。PP已开发 一个专有的HTS平台,使用FRET生物传感器和最先进的FLT-PR来检测结构 对于384孔板,读数在<2分钟内,对于1536孔板,读数在<5分钟内。通过与PP合作,我们将改变我们的 激酶FRET传感器技术成为识别AKI的广泛适用的药物发现平台。 我们提出了两个不同目标的药物发现计划,以证明广泛的效用和加速大规模的药物开发。 大规模采用我们的技术进行药物开发。在AIM 1中,我们鉴定了Aurora A抑制剂, 通过抑制Aurora A与c-Myc的支架相互作用,下调不可治疗的c-Myc癌蛋白。 Myc这些分子将代表一种新的治疗策略,用于大量的癌症患者, c-Myc驱动的肿瘤在AIM 2中,我们将c-MET受体酪氨酸激酶的变构抑制剂确定为一种新的 c-MET驱动的肺癌患者的治疗策略。这些患者总是对 目前的MET抑制剂通过ATP位点中的获得性突变,以及结合在细胞外的变构抑制剂, ATP位点将绕过这种耐药模式,满足未满足的临床需求。这种巫统-人民党伙伴关系 将莱文森和托马斯两位世界领先的专家数十年的生物物理学研究成果转化为药物, 通过解决激酶中配体驱动的变构来发现。这是由FLT-PR仪器实现的, 在分析中实现纳秒FLT检测所需的专有技术, HTS模式。这克服了传统激酶抑制剂筛选的关键缺点, 抑制或结合,而不考虑变构机制。该平台具有广泛的适用性,因为几乎所有 激酶经历了我们的技术检测到的大规模变构结构变化。成功的这项 该项目将促进这项技术的采用,目标是广泛的生物医学重要激酶, 光子制药与百时美施贵宝在药物发现方面的成功合作, 高优先级治疗目标。

项目成果

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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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