Thursday, April 25, 2024
4/25/2024
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.
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