Off-target mapping enhances selectivity of machine learning-predicted CK2 inhibitors

A key challenge in drug development is identification of druggable targets, the modulation of which attenuates disease progression, while avoiding inhibition of proteins that lead to dose-limiting toxicities. Here, we investigate a drug target casein kinase 2 (CK2) - a serine/threonine kinase implicated in cancer, for which existing inhibitors have so far failed in clinical trials. Using molecular and pharmacoepidemiology approaches, we show that small molecules targeting cyclin-dependent kinase (CDK) family members CDK1/2/7/9, including the existing CK2 inhibitors, have a higher risk to induce adverse effects or fail in clinical trials. Based on this finding, we establish a machine learning (ML) assisted discovery pipeline to redesign more specific and allosteric lead compounds against CK2, with a more selective on-target binding and favourable off-target profile. Importantly, we show that such selective design is possible when standard molecular docking and ML algorithms are combined with an error prediction model. In conclusion, our study reports a simple yet efficient ML-powered drug discovery pipeline and novel submicromolar inhibitors targeting clinically relevant CK2 kinase with no clinically approved antagonists available. Our prediction pipeline was able to achieve a 90% hit-rate, significantly reducing the need for subsequent wet-lab validation.