Crowdsourced mapping of unexplored target space of kinase inhibitors Academic Article uri icon

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benchmarking of predictive algorithms for kinase inhibitor potencies across multiple kinase families tested on unpublished bioactivity data.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.

author list (cited authors)

  • Tan, M., Huang, C., Shih, E., Chen, T., Wu, C., Fang, W., ... Šmuc, T.

complete list of authors

  • Cichońska, 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||Tan, Mehmet||Huang, Chih-Han||Shih, Edward SC||Chen, Tsai-Min||Wu, Chih-Hsun||Fang, Wei-Quan||Chen, Jhih-Yu||Hwang, Ming-Jing||Wang, Xiaokang||Ben Guebila, Marouen||Shamsaei, Behrouz||Singh, Sourav||Nguyen, Thin||Karimi, Mostafa||Wu, Di||Wang, Zhangyang||Shen, Yang||Öztürk, Hakime||Ozkirimli, Elif||Özgür, Arzucan||Lim, Hansaim||Xie, Lei||Kanev, Georgi K||Kooistra, Albert J||Westerman, Bart A||Terzopoulos, Panagiotis||Ntagiantas, Konstantinos||Fotis, Christos||Alexopoulos, Leonidas||Boeckaerts, Dimitri||Stock, Michiel||De Baets, Bernard||Briers, Yves||Luo, Yunan||Hu, Hailin||Peng, Jian||Dogan, Tunca||Rifaioglu, Ahmet S||Atas, Heval||Atalay, Rengul Cetin||Atalay, Volkan||Martin, Maria J||Jeon, Minji||Lee, Junhyun||Yun, Seongjun||Kim, Bumsoo||Chang, Buru||Turu, Gábor||Misák, Ádám||Szalai, Bence||Hunyady, László||Lienhard, Matthias||Prasse, Paul||Bachmann, Ivo||Ganzlin, Julia||Barel, Gal||Herwig, Ralf||Oršolić, Davor||Lučić, Bono||Stepanić, Višnja||Šmuc, Tomislav||Oprea, Tudor I||Schlessinger, Avner||Drewry, David H||Stolovitzky, Gustavo||Wennerberg, Krister||Guinney, Justin||Aittokallio, Tero

publication date

  • January 1, 2021 11:11 AM