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
• 负责人: Nicholas Mark Levinson
• 金额: $ 59.63万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10097782
• 关键词: Adoption; Affinity; Basic Science; Binding; Biochemical; Biological Assay; Biophysics; Biosensor; Cancer Patient; Cancer cell line; Chemicals; Clinical; Complex; Couples; Detection; Development; Disease; Dissociation; Exons; FDA approved; Fluorescence; Fluorescence Resonance Energy Transfer; Industrialization; Knowledge; Libraries; Ligands; MET gene; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Minnesota; Mission; Molecular Conformation; Monitor; Movement; Mutation; Oncology; Oncoproteins; Patients; Phosphotransferases; Proto-Oncogene Proteins c-myc; Reader; Receptor Protein-Tyrosine Kinases; Regulatory Element; Research; Resistance; Resistance development; Site; Structure; Technology; Testing; Therapeutic; Translating; Ubiquitination; Universities; Validation; base; c-myc Genes; crizotinib; drug development; drug discovery; field study; follow-up; high throughput screening; industry partner; inhibitor/antagonist; innovation; instrumentation; kinase inhibitor; nanosecond; next generation; novel; novel strategies; novel therapeutic intervention; novel therapeutics; photonics; prevent; programs; resistance mutation; scaffold; sensor; sensor technology; small molecule; success; technology development; therapeutic target; treatment strategy; tumor; tumorigenesis

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Photonic Pharma（PP）一家位于明尼苏达州的药物发现初创公司 合作以优化，现场测试和以工业规模部署，这是一种创新的开发新方法 变构激酶抑制剂（AKI）。这些分子作为新型癌症治疗具有很高的潜力 规避临床对常规直角激酶抑制剂（OKI）的抗性。我们已经开发了高 基于纳秒荧光寿命（FLT）检测Förster的吞吐量筛选（HTS）技术 共振能量传递（FRET），该能量传递以埃轴的精度跟踪配体驱动的激酶变构酶 监测激活环的结构变化，这是所有激酶的关键调节元件。这是第一个 依靠高质量的HTS无限技术，可准确解决激酶抑制剂的变构效应 纳秒FLT读数无法从常规荧光板读取器（PR）中获得。 PP已经发展 专有的HTS平台，使用FRET生物传感器和最先进的FLT-PR检测结构 <2分钟的读数为384孔，1536孔板<5分钟。通过与PP合作，我们将改变我们的 激酶FRET传感器技术成为一个广泛适用的药物发现平台，用于识别Akis。 我们提出针对两个不同目标的药物发现计划，以证明广泛的效用，并加速了大型效用 规模采用我们的药物开发技术。在AIM 1中，我们确定Aurora A抑制剂 通过抑制Aurora a与C-的脚手架相互作用来下调不良的C-Myc癌蛋白 妈妈。这些分子将代表大量癌症患者的新型治疗策略 C-MYC驱动的肿瘤。在AIM 2中，我们确定C-MET受体酪氨酸激酶的变构抑制剂是一种新颖 C-MET驱动肺癌患者的治疗策略。这些患者总是会产生对 当前通过在ATP部位获得的突变遇到抑制剂，以及结合在外部的变构抑制剂 ATP站点将避免这种阻力模式，从而满足未满足的临床需求。这种UMN-PP合作伙伴关系 将两位世界领先的专家-Levinson和Thomas的数十年的生物物理学研究翻译成毒品 - 通过解决激酶中的配体驱动的变构来发现。这是由FLT-PR仪器和 在解决变构抑制剂的测定中实施纳秒FLT检测所需的专业知识 HTS模式。这克服了传统激酶抑制剂筛选的关键缺点，该筛选检测激酶 抑制或结合，无需考虑变构机制。该平台广泛适用，因为几乎全部 激酶经历了我们技术检测到的大规模变构结构的变化。成功的成功 项目将催化针对广泛的生物医学重要激酶的这项技术的采用，作为 Photonic Pharma与Bristol-Myers Squibb的成功伙伴关系突出显示了其他 高优先级治疗靶标。