A1 Refereed original research article in a scientific journal

Crowdsourced mapping of unexplored target space of kinase inhibitors




AuthorsCichońska Anna, Ravikumar Balaguru, Allaway Robert J., Wan Fangping, Park Sungjoon, Isayev Olexandr, Li Shuya, Mason Michael, Lamb Andrew, Tanoli Ziaurrehman, Jeon Minji, Kim Sunkyu, Popova Mariya, Capuzzi Stephen, Zeng Jianyang, Dang Kristen, Koytiger Gregory, Kang Jaewoo, Wells Carrow I., Willson Timothy M.; The IDG-DREAM Drug-Kinase Binding Prediction Challenge Consortium, Oprea Tudor I., Schlessinger Avner, Drewry David H., Stolovitzky Gustavo, Wennerberg Krister, Guinney Justin, Aittokallio Tero

PublisherNATURE RESEARCH

Publication year2021

JournalNature Communications

Journal name in sourceNATURE COMMUNICATIONS

Journal acronymNAT COMMUN

Article numberARTN 3307

Volume12

Issue1

Number of pages18

ISSN2041-1723

eISSN2041-1723

DOIhttps://doi.org/10.1038/s41467-021-23165-1

Web address https://www.nature.com/articles/s41467-021-23165-1

Self-archived copy’s web addresshttps://research.utu.fi/converis/portal/detail/Publication/66381636


Abstract

Despite decades of intensive search for compounds that modulate the activity of particular protein targets, a large proportion of the human kinome remains as yet undrugged. Effective approaches are therefore required to map the massive space of unexplored compound-kinase interactions for novel and potent activities. Here, we carry out a crowdsourced benchmarking of predictive algorithms for kinase inhibitor potencies across multiple kinase families tested on unpublished bioactivity data. We find the top-performing predictions are based on various models, including kernel learning, gradient boosting and deep learning, and their ensemble leads to a predictive accuracy exceeding that of single-dose kinase activity assays. We design experiments based on the model predictions and identify unexpected activities even for under-studied kinases, thereby accelerating experimental mapping efforts. The open-source prediction algorithms together with the bioactivities between 95 compounds and 295 kinases provide a resource for benchmarking prediction algorithms and for extending the druggable kinome. The IDG-DREAM Challenge carried out crowdsourced benchmarking of predictive algorithms for kinase inhibitor activities on unpublished data. This study provides a resource to compare emerging algorithms and prioritize new kinase activities to accelerate drug discovery and repurposing efforts.


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