Dual-target kinase drug design: Current strategies and future directions in cancer therapy

Protein kinases are well-known to orchestrate the activation of signaling cascades in response to extracellular and intracellular stimuli to control cell proliferation and survival. The perturbation of such kinases by some mutation or abnormal protein expressions has been closely linked to cancer. Drug development aimed at several targetable kinases may alter their participated pathways that are able to trigger carcinogenesis. A series of small-molecule drugs have been approved for the current cancer therapy. However, their complicated inherent mechanisms may lead to the resistance to such small molecules. Consequently, development of new dual-target kinase drugs simultaneously aimed at two targetable kinases may improve their anti-tumor efficiency and solve resistant mechanism problems. In this review, we focus on summarizing an overview of the current strategies of dual-target kinase drug design, including medicinal chemistry strategies and computational approaches. Taken together, we believe the above-mentioned strategies will provide a new insight into future directions of dual-target kinase drug design to improve potential cancer therapeutics. (C) 2020 Elsevier Masson SAS. All rights reserved.