Abstract
Drug Mechanism of Action (MoA) is generally represented as a small repertoire of tissue-independent, high-affinity binding targets. Yet, drug activity and polypharmacology are associated with a broad range of off-target and tissue-specific effector proteins. To address this challenge, we have generated a compendium of drug perturbation profiles for >700 oncology drugs in cell lines representing high-fidelity models of 23 aggressive tumor subtypes and developed an integrative computational framework for the proteome-wide assessment of drug-mediated, tissue-specific differential protein activity. This allows systematic, mechanism-based elucidation of tissue context-specific compound MoA and polypharmacology, including discovery and experimental validation of post-translationally-mediated inhibition of undruggable oncoproteins-such as MYC, CTNNB1, CENPF and UHRF1-as well as previously unknown inhibitors of MAPK, PI3K, and folate pathways, among others, as further suggested by protein structure analysis. This framework can help characterize the MoA of discovery compound libraries, thus supporting more systematic and quantitative approaches to precision oncology.