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: 10595089
• 负责人: Nicholas Mark Levinson
• 金额: $ 57.17万
• 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/10595089
• 关键词: Acceleration; Adoption; Affinity; Basic Science; Binding; Biochemical; Biological Assay; Biophysics; Biosensor; Cancer Patient; Cancer cell line; Chemicals; Classification; 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; Technology; Testing; Therapeutic; Translating; Ubiquitination; Universities; Validation; c-myc Genes; crizotinib; drug development; drug discovery; field study; follow-up; high throughput screening; industry partner; inhibitor; 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.

项目概要 明尼苏达大学 (UMN) 和 Photonic Pharma (PP) 是一家位于明尼苏达州的药物发现初创公司， 合作优化、现场测试和工业规模部署，这是一种创新的开发方法 变构激酶抑制剂（AKI）。这些分子具有作为新型癌症疗法的巨大潜力 规避对传统正构激酶抑制剂（OKI）的临床耐药性。我们开发了高 Förster 基于纳秒荧光寿命 (FLT) 检测的通量筛选 (HTS) 技术 共振能量转移（FRET），通过埃的精度追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节元件。这是第一个 适合 HTS 的技术，依靠高质量准确解决激酶抑制剂的变构效应 传统荧光读板器 (PR) 无法提供纳秒级 FLT 读数。 PP已经开发出来 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 384 孔板可在 2 分钟内读出读数，1536 孔板可在 5 分钟内读出读数。通过与 PP 合作，我们将改变我们的 激酶 FRET 传感器技术成为广泛适用的药物发现平台，用于识别 AKI。 我们提出针对两个不同目标的药物发现计划，以展示广泛的效用并加速大规模应用 大规模采用我们的药物开发技术。在 AIM 1 中，我们鉴定出 Aurora A 抑制剂 通过抑制 Aurora A 与 c- 的支架相互作用来下调不可成药的 c-Myc 癌蛋白 米克。这些分子将为大量癌症患者提供一种新的治疗策略 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型药物 c-MET 驱动的肺癌患者的治疗策略。这些患者总是会产生耐药性 目前的 MET 抑制剂通过 ATP 位点的获得性突变，以及结合在 ATP 位点外部的变构抑制剂 ATP 位点将规避这种耐药模式，满足未满足的临床需求。 UMN-PP 合作伙伴关系 将两位世界领先的专家莱文森和托马斯数十年的生物物理学研究转化为药物 通过解决激酶中配体驱动的变构来发现。这是通过 FLT-PR 仪器实现的 在真正解析变构抑制剂的测定中实施纳秒 FLT 检测所需的专业知识 高温超导模式。这克服了传统激酶抑制剂筛选的主要缺点，传统激酶抑制剂筛选检测激酶 抑制或结合，而不考虑变构机制。该平台适用范围广泛，几乎所有 激酶经历我们的技术检测到的大规模变构结构变化。此次成功 该项目将促进针对广泛的生物医学重要激酶的这项技术的采用，例如 Photonic Pharma 与百时美施贵宝在其他药物发现方面的成功合作伙伴关系凸显了这一点 高优先级的治疗目标。