Trends in Pharmacological Sciences
Feature ReviewFDA-approved small-molecule kinase inhibitors
Section snippets
Kinase inhibitors: a burgeoning field
The past one and a half decades witnessed an unparalleled success in the development of therapeutically useful kinase inhibitors, powered by tremendous progress in both academic and industrial settings. The milestone approval of the first kinase inhibitor, imatinib, in 2001 by the FDA, was followed by a slow yet steady approval of kinase inhibitors in the first 10 years of this century with almost one new approval per year on average. Concurrently, our understanding of kinase signaling networks
Kinases
Kinases catalyze the transfer of the γ-phosphate group of ATP onto a substrate, mediate most signal transductions [1], and regulate various cellular activities, including proliferation, survival, apoptosis, metabolism, transcription, differentiation, and a wide array of other cellular processes [2]. Accumulating pharmacological and pathological evidence has revealed that kinases are promising drug targets for the treatment of numerous diseases [3] such as cancers 4, 5, 6, inflammatory diseases 7
Kinase inhibitors
Although diverse in primary amino acid sequence, the human kinases share a great degree of similarity in their 3D structures, especially in their catalytically active kinase domain where the ATP-binding pocket is located: a β sheet containing N-terminal lobe (N-lobe), an α helix-dominated C-terminal lobe (C-lobe), and a connecting hinge region [21]. ATP binds in the cleft formed between the N- and C-lobes and most kinase inhibitors perturb binding through interactions with this region. A
Reversible non-receptor tyrosine kinase (NRTK) inhibitors
BCR-Abl was the first kinase for which a small-molecule inhibitor was successfully approved [32]. On another note, being the first approved kinase inhibitor and a revolutionary success for the treatment of chronic myeloid leukemia (CML) [17], imatinib has been the subject of various SAR studies to guide the design of next-generation inhibitors and provide a deeper understanding of the inhibition mechanism. Considerable efforts seek to develop inhibitors based on structural features derived from
Approved irreversible protein kinase inhibitors
The EGFR inhibitor afatinib was the first clinically approved irreversible kinase inhibitor, followed shortly by ibrutinib in November 2013. The approval of these two molecules validates the strategy of incorporating Michael acceptor functionality in small-molecule inhibitors to form a covalent bond with a cysteine residue in the active site of kinases. This type of irreversible inhibitor is expected to achieve greater specificity and potency, although concerns have been raised regarding
Approved serine/threonine kinase inhibitors
The serine/threonine kinase B-Raf, one of the three isoforms of the Raf family, has been established as an attractive anticancer target [81]. Replacement of Val600 with Glu600 within the activation loop of the kinase domain accounts for 90% of B-Raf mutations [82], resulting in destabilization of the inactive conformation, elevated activation of the MAPK pathway, and enhanced promotion of cell survival and proliferation. Efforts in developing small-molecule kinase inhibitors led to the approved
Approved lipid kinase inhibitors
Lipid kinases, such as PI3Ks, were discovered as early as the 1980s [95]. It has been convincingly established that activation and mutation of PI3Ks and other key components of this signaling pathway play key roles in various stages of tumor development [96]. Considerable efforts from both academia and industry have been involved in the development of small-molecule lipid kinases since the 1980s, but the clinical success of these inhibitors was minimal until the approval of the first lipid
Limitations and challenges
Kinase-based drug discovery has achieved dramatic progress in the past 15 years. Although kinase inhibition represents a young therapeutic strategy compared with other, traditional tactics targeting, for example, G protein-coupled receptors (GPCRs), membrane channels and transporters, and protease, an analysis of FDA-approved cancer drugs since the 1980s reveals that kinases have already overtaken GPCRs as the most sought-after cellular targets for cancer treatment [108]. Our analysis of all
Future directions
Based on the current trends discussed above, some challenging questions that might serve as directions for future development of small-molecule kinase inhibitors and push the boundary of the research in this field need to be addressed appropriately.
First, the fact that current kinase inhibitors focus on only a small subset of the human kinome indicates that many kinases are neglected. Thus, there is a need to develop tools and selective probes to uncover the functions of these unknown kinases
Concluding remarks
Groundbreaking understanding of cellular signaling cascades at the molecular level has led to major advances in kinase research over the past decades. The dramatic progress in applying the strategy of targeted kinase inhibition in the past 15 years has been highlighted by the successful approval of no less than 28 small-molecule kinase inhibitors. An analysis based on co-crystal structures of all approved inhibitors with a focus on binding mechanism and structural features is presented here to
Acknowledgements
The Lundbeck Foundation (R140-2013-13835) is gratefully acknowledged for financial support. The authors thank Professor David A. Tanner for proofreading the manuscript.
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