Compound Mechanism of Action and Polypharmacology can be Elucidated by Large-Scale Perturbational Profile Analysis

Drug Mechanism of Action (MoA) is often represented as a small repertoire of tissue-independent, high-affinity binding targets. Yet drug activity and polypharmacology are also manifested through a broad range of off-target and tissue-specific effector proteins. To address this dichotomy, we generated a compendium of drug perturbation profiles for >700 oncology drugs in cell lines representing high-fidelity models of 23 aggressive tumor subtypes, as well as an integrative framework for the proteome-wide assessment of drug-mediated, tissue-specific differential protein activity. Extending MoA and polypharmacology assessment via proteome-wide, multi-tissue analyses revealed novel polypharmacolo