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Developing a Proteomics-based Off-target Identification Assay to Inform Safety Pharmacology Profiling of Targeted Protein Degraders
Sarah Ingersoll, PhD, Amgen

Comparative Effects in Delaying Repolarization by Small Molecules and an Oligonucleotide in Stem Cell Derived Cardiomyocytes
Yusheng Qu, PhD, Amgen Inc.

January 30 at 11:00 AM Eastern

Targeted protein degraders (TPDs) are a novel therapeutic modality that harnesses the ubiquitin-proteasome system to selectively degrade proteins of interest. While TPDs offer an innovative approach in drug discovery, these molecules may inadvertently alter the expression of off-target proteins, potentially leading to safety risks. Secondary pharmacology assays for pharmaceuticals, which evaluate the binding or function against off-target proteins, do not fully address the impact of potential off-target degradation by TPDs. This presentation will outline the development of a novel in vitro assay, where off-target proteins of interest were systematically prioritized from the entire human proteome based on phenotypes from genetic and pharmacological evidence, collectively termed the selected off-target proteome (SOTP). Human cell lines were selected to maximize the SOTP transcriptome coverage, while SOTP protein coverage was quantified in these cell lines using global proteomics. The performance of the assay was evaluated using positive control TPD molecules. The proteomics-based off-target identification assay is a new platform that complements conventional secondary pharmacology assays for pharmaceuticals to address in vitro safety pharmacology evaluation of TPD molecules.

Moderator:  Ziva Arimura, BS, Amgen

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