Deep learning is a machine learning technique that attempts to model high-level abstractions in data by utilizing a graph composed of multiple processing layers that experience various linear and non-linear transformations. This technique has been shown to perform well for applications in drug discovery, utilizing structural features of small molecules to predict activity. However, the application of deep learning to discriminating features of kinase inhibitors has not been well explored. Small molecule kinase inhibitors are an important class of anti-cancer agents and have demonstrated impressive clinical efficacy in several different diseases. However, resistance is often observed mediated by adaptive Kinome reprogramming or subpopulation diversity.Therefore, polypharmacology and combination therapies offer potential therapeutic strategies for patients with resistant disease. Their development would benefit from more comprehensive and dense knowledge of small-molecule inhibition across the human Kinome. Because such data is not publicly available, we evaluated multiple machine learning methods to predict small molecule inhibition of 342 kinases using over 650K aggregated bioactivity annotations for over 300K small molecules curated from ChEMBL and the Kinase Knowledge Base (KKB). Our results demonstrated that multi-task deep neural networks outperform classical single-task methods, offering potential towards predicting activity profiles and filling gaps in the available data. ANCILLARY INFORMATIONSupporting Information. Author ContributionsBKA. developed code, performed computational modeling and data analysis; data curation and data integration; BKA and SCS performed data curation and integration; SCS devised the project; SCS and NA advised the project; BKA and SCS wrote the manuscript.