Abstract 3092: MICRO-TAG: A novel fluorescence-based real-time cellular target engagement platform for drug discovery

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Abstract Success of drug discovery programs can be amplified by adopting emerging technologies that can interrogate drug targets within their physiological context. Cell target engagement (CTE) presents a combined biological & biophysical method, which provides quantitative evaluation of target-drug interaction within the native environment of the cell. The currently available luminescence-based CTE methods are limited to measurement of end-point signal and poor resolution, thereby limiting their mechanistic and stoichiometric insight. We have developed MICRO-TAG, a novel fluorescence-based CTE platform, which relies on complementation of split-RNAse A. It enables interrogation of target engagement without interfering with folding, localization and function of target proteins - all within the physiological milieu of the cell. Uniquely, this new platform allows for quantitation and monitoring of CTE in real- time in the cell. It enables extraction of important parameters from target-drug interaction: target thermal profile and temperature of aggregation (Tagg), time required to reach equilibrium (teq), apparent association rate (Kon) and physiologically relevant drug:target binding affinity (KD). We provide data demonstrating potential and utility of MICRO-TAG platform on drug targets, such as KRAS, MTH1, EGFR, and UBE2N. The platform demonstrates relevance for discovery of novel drug candidates targeting challenging drug targets such as transcription factors. This highly scalable and quantitative novel method for assessing drug-target interaction within cells can enhance drug discovery programs, and offers potential to rapidly identify clinically relevant hit compounds for challenging drug targets. Citation Format: Ivan Babic, Nikolas Bryan, Claire Cunningham, Avery Sampson, Daniel Starczynowski, Elmar Nurmemmedov. MICRO-TAG: A novel fluorescence-based real-time cellular target engagement platform for drug discovery [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3092.

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