(1007-D) A Rapid, High-Throughput and Effective Process for Identifying Molecular Glues Using Affinity Selection Mass Spectrometry (ASMS)
Tuesday, February 6, 2024
2:00 PM – 3:00 PM EST
Location: Exhibit Halls AB
Abstract: Targeted protein degradation (TPD) is an important therapeutic mechanism to engage challenging and previously intractable protein targets. Within this modality, molecular glues have attracted a significant and growing interest. Traditionally, the identification of molecular glues has been limited by serendipitous discovery and a lack of systematic evaluations. Alternatively, current assay methodologies often rely on label-dependent binding assays that are cumbersome, tedious, and unreliable. Hence, the current challenge for molecular glue-induced TPD is high-throughput assay methodology to screen these compounds against any target. To address this shortcoming, we utilize a novel, label-free and high-throughput affinity selection mass spectrometry (ASMS) method with unique benefits for molecular glue discovery. The technique benefits from defined surface chemistry that offers the fastest ASMS workflow, enabling the screening of libraries with minimal library compression to decrease false positive rates, and is amenable to virtually any target, including complexes. Moreover, to focus our screening efforts we have assembled a >5,000-member small molecule compound library, possessing key structural motifs from four known molecular glue chemotypes. Here, we demonstrate that the combination of the assay methodology and compound collection opens avenues to accelerate the discovery of molecular glues and offers new insight into this emerging therapeutic modality.