Introduction to Kinase Antitargets

Kinases represent an important enzyme class in drug discovery. They control cellular communication via distinct signaling networks. This is tightly regulated through transfer of phosphate from high‐energy adenosine triphosphate (ATP) onto the hydroxyls of serine, threonine, or tyrosine residues in specific protein substrates. This leads to amplification of signals and control of downstream functions or activation of transcription factors, resulting in a cellular phenotypic response (e.g., proliferation, angiogenesis, migration, and differentiation). More than 400 human diseases have been connected either directly or indirectly to protein kinases. At least 10 000 relevant patent applications have been filed in the last decade. Through the end of 2013, 26 small molecules and 7 large molecules have been approved by the US Food and Drug Administration (FDA), with the majority of these agents registered for use in oncology. This section updates the kinase state of the art, with a focus on selectivity and toxicity (preclinical and clinical). The authors shed light on this balance based on significant experience in the field and extensive literature analysis, and hope to leave readers with a deeper appreciation for the complexity of the area and provide insights into identifying safer and more effective kinase drugs.