Editorial pubs.acs.org/jmc
Advancing the Kinase Field: New Targets and Second Generation Inhibitors t is a great pleasure to introduce the special issue “New Frontiers in Kinases”. When planning this special issue for the Journal of Medicinal Chemistry in collaboration with three other American Chemical Society journals (ACS Chemical Biology, ACS Medicinal Chemistry Letters, and Biochemistry), our expectations were high. Kinases represent one of the most heavily hit therapeutic target families, and a primary goal of this publication project was to reach beyond the beaten path of more or less promiscuous ATP-site directed inhibitors that have dominated this field until recently. These types of small molecular inhibitors have substantially advanced the treatment of a variety of cancers and are, without doubt, among the premier success stories of drug discovery research. Reaching beyond these successes in an increasingly mature kinase field meant to specifically focus, first and foremost, on new kinase targets (as the currently most popular kinases only represent ∼20% of the human kinome) and the generation of novel types of inhibitors that are more selective or specific, especially for the treatment of chronic immune diseases. More than efficacy, safety is a major challenge for such inhibitors. Lifelong treatment of a typically nonlethal disease competing with existing therapies puts the hurdle for kinase drug discovery substantially higher. Furthermore, the discussion of new concepts for kinase research and drug development was explicitly encouraged. Tremendous progress in structural biology and bioinformatics over the past decade gives medicinal chemists today a well filled toolbox for the design of improved inhibitors. The interest in this initiative was high. The special issue contains over 30 contributions, including perspectives and research articles, from groups in academia and the pharmaceutical industry, and indeed represents what we had wished for. Even more, the creativity of medicinal chemistry went much further than might have been expected. The papers in this issue cover a broad spectrum of studies and provide a detailed view of state-of-the-art activities in the kinase field aiming to enter new territory. The methodological diversity with which kinase inhibitor discovery is approached represents a striking feature of this special issue. In addition to high-level medicinal chemistry efforts, instructive examples of structural studies, structure-based design, computational analysis and predictions, pharmacological studies, and various biological investigations are presented. Often, the research has been carried out in a highly interdisciplinary manner, combining a variety of approaches. In particular, a number of contributions from the pharmaceutical industry provide detailed views of drug discovery projects, far beyond what was known publicly, and the interplay of different approaches in the design and development of new kinases inhibitors. It would go much beyond the scope of an editorial to comment in detail on all studies contained in this special issue (although it would certainly be deserved). Hence, we limit our introductory comments to just a few representative investigations that are very much in line with the theme and aims of
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this issue. For example, among the perspective articles, Chaudhary et al. highlight inhibitors of interleukin-1 receptorassociated kinase 4, an emerging and widely considered serine/ threonine kinase target in inflammation and oncology, and Rudolph et al. focus on inhibitors of P21-activated kinases, another family of serine/threonine kinases implicated in infectious and neurological diseases, in addition to cancer development. Among instructive examples of interdisciplinary drug discovery research are studies by Carry et al., reporting the design of a selective inhibitor of Aurora serine/threonine kinases (oncology targets), and by Henderson et al., who describe the development of a selective inhibitor of leucine rich repeat kinase 2, a tyrosine kinase implicated in Parkinson’s disease. In addition, an example of type I kinase inhibitor optimization based upon computational analysis and design is provided by Horbert et al., and Tan et al. report the discovery of type II inhibitors with dual activity against two mitogenactivated kinases on the basis of focused library screening and X-ray crystallography. Furthermore, George et al. describe the evolution of a selective inhibitor of protein kinase C θ from a fragment hit for the treatment of chronic inflammatory diseases. These representative studies provide a flavor of the diverse and exciting science in emerging areas of the kinase field assembled in the special issue. Most of all, we thank our authors for their many outstanding contributions. We also thank numerous reviewers of submissions to the special issue who often have on rather short notice diligently evaluated manuscripts. Furthermore, special thanks go to the editors of the Journal of Medicinal Chemistry and the editorial office staff for their continuous support of this project. Last but not least, we very much hope that the readers of the Journal of Medicinal Chemistry will enjoy this special issue on kinases and their inhibitors and the scientific advances it represents.
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Stefan Laufer, Editorial Advisory Board Member Jürgen Bajorath, Associate Editor
AUTHOR INFORMATION
Notes
The views expressed in this editorial are those of the authors and not necessarily the views of the ACS.
Special Issue: New Frontiers in Kinases
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dx.doi.org/10.1021/jm5018708 | J. Med. Chem. XXXX, XXX, XXX−XXX
