Dysfunctional cell signalling caused by deregulation of kinases is a major cause of cancer.  A new kinase-inhibitory scaffold containing a motif capable of forming the necessary hydrogen bonds to the hinge region, 1  , has been designed.   This scaffold has been synthesised using a modified rhodium-catalysed cyclisation-cycloaddition-ring opening cascade reaction via an isom�nchnone intermediate (3  ). Scaffold 4  has been tested against a large number of kinases using a variety of biochemical and biophysical assays, and was found to inhibit several kinases, some of which are well studied in cancer and others are emerging therapeutic targets.  Scaffold derivitization has also yielded more potent hits against these kinases.  X-Ray crystallography and in silico docking is being used to determine the binding mode of these compounds and to drive the design of more potent and selective compounds.

New structural templates for kinase inhibition

243rd National Meeting (2012)

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