Integrative pharmacogenomics to infer large-scale drug taxonomy

ABSTRACT Identification of drug targets and mechanism of action (MoA) for new and uncharacterlzed drugs is important for optimization of drug efficacy. Current MoA prediction approaches largely rely on prior information including side effects, therapeutic indication and/or chemo-informatics. Such information is not transferable or applicable for newly identified, previously uncharacterlzed small molecules. Therefore, a shift in the paradigm of MoA predictions is necessary towards development of unbiased approaches that can elucidate drug relationships and efficiently classify new compounds with basic input data. We propose a new integrative computational pharmacogenomlc approach, referred to as Drug Network Fusion (DNF), to infer scalable drug taxonomies that relies only on basic drug characteristics towards elucidating drug-drug relationships. DNF is the first framework to integrate drug structural information, high-throughput drug perturbation and drug sensitivity profiles, enabling drug classification of new experimental compounds with minimal prior information. We demonstrate that the DNF taxonomy succeeds in identifying pertinent and novel drug-drug relationships, making it suitable for investigating experimental drugs with potential new targets or MoA. We highlight how the scalability of DNF facilitates identification of key drug relationships across different drug categories, and poses as a flexible tool for potential clinical applications in precision medicine. Our results support DNF as a valuable resource to the cancer research community by providing new hypotheses on the compound MoA and potential insights for drug repurposlng.