Structural approaches to obtain kinase selectivity |
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Authors: | Norman Richard A Toader Dorin Ferguson Andrew D |
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Institution: | Discovery Sciences, AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK. richard.norman@astrazeneca.com |
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Abstract: | One of the grand challenges in kinase drug discovery is the design of small-molecule inhibitors with selectivity profiles that will ultimately be efficacious in the clinic. Current medicinal chemistry strategies make heavy use of structural, biophysical and computational approaches to achieve this multi-faceted goal. Here we review structure-based approaches underlying the development of several molecules that are currently in clinical trials, including the cMet inhibitor ARQ197 and the Bcr-Abl inhibitor ponatinib. We highlight the challenge posed by the emergence of resistance mutants and discuss promising lead generation strategies to obtain selective inhibitors of protein and lipid kinases such as targeting of specific sites, the use of fragment-based approaches and new chemical probes based on metal complexes. |
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