Abstract
Abstract E3 ligases have emerged as pivotal targets for a next generation protein degradation-based drug discovery paradigm. This new paradigm includes both ligand binding-directed “reprogramming” of E3 substrate specificity approaches and a more directed approach, using small molecule proteolysis-targeting chimeras (PROTACs), to selectively degrade disease-driving proteins. As there are hundreds of diverse putative E3 ligases with differentiated tissue expression, this new paradigm may well define a next dimension of precision medicine defined by an axis of tissue-specific activity. While there have been some early successes, the E3 drug discovery field has a significant unmet need for a standardized biochemical ligand binding assay platform. A platform is required that: 1) Can measure ligand binding across the E3 family using a standardized method enabling “apples to apples” comparisons; 2), Is highly scalable and rapid; 3) Has an exquisite dynamic range for the measurement of accurate KD values as low as digit picomolar (pM). Eurofins DiscoverX herein presents its novel E3scan™ technology that addresses each of these unmet needs. E3scan, based upon well-established KINOMEscan® technology, has been successfully applied to diverse E3 ligases, including CRBN, VHL, MDM2, MDMX, cIAP1, cIAP2, and XIAP, with many other E3 assays in progress. We shall present assay validation data for these targets, including data for ligands with KD values in the low to mid pM range. In conclusion, we present Eurofins DiscoverX's novel E3scan platform that shall enable accelerated screening and SAR analysis in the E3 drug discovery field, with rapid turnaround times for discovery library screens (20 business day TAT) and weekly SAR (5 business day TAT) and the largest assay panel available on a single technology platform. Citation Format: Ksenya Cohen Katsenelson, Luis Gonzalez, Gabriel Pallares, Alastair J. King, Daniel K. Treiber. E3scan™ ligand binding assay platform for targeted protein degradation and PROTAC discovery [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6408.
Published Version
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