oa Editorial [Hot Topic: Protein Kinase Inhibitors: Current Strategies and Future Prospects (Executive Guest Editor: Julio Caballero)]

Protein kinases (PKs) play key roles in signal transduction pathways. Therefore, aberrant PK activity can cause significant alterations in many important cellular processes such as transcription, proliferation, differentiation, angiogenesis, and inhibition of apoptosis, thereby contributing to a variety of illnesses including cancer, metabolic disorders, inflammation, autoimmune diseases, diabetes, etc [1]. More than 1000 X-ray crystal structures indicate that all PKs share certain structural similarities, comprising a small N-terminal lobe and a larger Cterminal lobe, with a highly conserved catalytic domain. ATP adjusts perfectly in a cleft between the lobes, and the protein substrate binds at the entrance of the cleft. PKs catalyze the transfer of the terminal γ-phosphate of the ATP to the hydroxyl group on the side chains of tyrosine, serine, or threonine residues of the substrate proteins. Phosphorylation results in a conformational change in the structure in many enzymes and receptors, causing them to become activated or deactivated. The discovery of PK inhibitors has attracted growing interest for novel drugs research and development [2]. The success of smallmolecule such as imatinib, nilotinib, and dasatinib for the treatment of chronic myelogenous leukemia, sunitinib and sorafenib for the treatment of renal cell carcinoma, gefitinib and erlotinib for the treatment of non-small-cell lung cancer, and lapatinib for the treatment of breast cancer and other solid tumours, confirm that ATP-competitive inhibitors are effective [3-5]. The discovery of ATP-competitive PK inhibitors has increased exponentially in the last years. Emerging knowledge of the both structure and the mechanism of action and modulation of PKs provided clues for the development of the new inhibition strategies. The design of ATP-competitive PK inhibitors faces a challenging selectivity problem because of the high structural homology between the ATP-binding site of PKs. Therefore, some novel strategies have been identified to explote other functionally critical binding sites. These approaches include substrate competitive inhibitors and targeting of allosteric sites that stabilize inactive conformations, and non-catalytic domains [6]....