Kinase inhibition – applications in drug discovery

In the Pharmaceutical arena, the field of kinases has been the subject of a great deal of interest over the past decade and perhaps even longer. This is perhaps not surprising when one considers the vast array of biological systems that are modulated through specific phosphorylation/dephosphorylation events.

As one might imagine, a significant amount of effort has been focused on cancer, where there are a huge number of kinases potentially involved in the multiplicity of signalling pathways. Although there has been a significant focus on cancer, there have been a number of other areas in which targeting kinases has brought success and breakthroughs, particularly AIDS, diabetes, inflammation, cardiovascular disease, bipolar disorder and neuronal degeneration, to name but a few.

In this issue of Drug Discovery Today, Editor’s Choice, we will be highlighting some of the recent developments and breakthroughs in kinase drug targets. The papers we feature are all available as free downloads, so please have a look at them; I’m sure that you will find them both accessible and interesting. The most recent article is from Fabrizio Manetti, who addresses the area of LIM kinases and how the development of inhibitors of these enzymes might be a successful approach to the treatment of AIDS.

In the next article, Yan-Jie Zhang, Yanwen Duanand X.F. Steven Zheng discuss the development of second generation inhibitors of mTOR through inhibition of the mTOR kinase domain in the development of novel cancer drugs. As the authors point out, about 50% of all malignancies have a dysregulated mTOR signaling pathway, so development of compounds addressing this important kinase may have broad application. The reason why the mTOR kinase domain has been targeted for the development of second generation drugs is that it is important for both rapamycin-sensitive and -insensitive functions of the signaling pathway.

Following on from this, Da-Qing Yang, Marie-Jo Halaby, Yan Li, Jody C. Hibma and Paul Burn introduce another kinase target, the cytoplasmic ATM protein kinase. This target is a serine/threonine protein kinase. Its substrate, ATM, has been implicated in the pathogenesis of Ataxia–telangiectasia (A–T). It has been shown that mutations in the gene for this protein can result in deletion or inactivation of the protein. Individuals with impairment in ATM function frequently demonstrate symptoms in childhood such as altered gait and coordination as a result of the degeneration of the cerebellar cortex. These early symptoms may later be accompanied by a predisposition to cancer, immune deficiency, growth retardation, premature

aging, insulin resistance and glucose intolerance.  It is proposed that by targeting ATM kinase, it is possible that therapies addressing a wide range of diseases could potentially be developed.
Finally, Aixia Yan, Liyu Wang, Shuyu Xuand Jun Xu examine and explore some of the more chemical aspects of the development of Aurora kinase inhibitors in their article: “Aurora-A kinase inhibitor scaffolds and binding modes”. In this article, the authors highlight hotspot residues in the binding sites and privileged inhibitor structures. This article will be of great interest to medicinal chemists involved in the development of inhibitors of Aurora kinases, but also of general interest to chemists involved in the discovery of anti-cancer agents.
I hope that you enjoy the articles offered in this newsletter; I’d be glad to receive any comments about this, or on future topics that you think we could address.
Steve Carney was born in Liverpool, England in 1957 and studied Biochemistry at Liverpool University (1975-1978), obtaining a BSc.(Hons) and then read for a PhD on the Biochemistry and Pathology of Connective Tissue Diseases in Manchester University, in the Departments of Medical Biochemistry and Histopathology (1978-1981). On completion of his PhD he moved to the Kennedy Institute of Rheumatology, London in 1981, where he worked with Professor Helen Muir FRS and Professor Tim Hardingham, on the biochemistry of experimental Osteoarthritis. In 1987, he joined Eli Lilly and Co. and held a number of positions in Biology R&D, initially in the Connective Tissue Department, but latterly in the Neuroscience Department. He left Lilly in 2002 to take up his present position as Managing Editor, Drug Discovery Today, at Elsevier. He has authored over 40 peer-reviewed articles, written several book chapters and has held a number of patents.

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