Protein kinases display a considerably higher conformational variability in their unactive or inactive state that in their active state. Hence in/unactive forms of kinases are attractive targets for drug design. Their conformational variability can be the basis for more selective inhibitors, which are difficult to achieve given that all active kinases have an ATP-binding pocket with some high degree of homology.
The recently described inhibitory mechanism of STI571 (Gleevec, Imanitib) by binding to an inactive form of Abl tyrosine kinase and preventing its activation provides an exciting approach for designing new highly specific inhibitors. STI571 has proven to be highly selective - inhibiting only PDGFR, ARG and c-Kit - with potencies comparable to that of Abl. Notably STI576 does not inhibit the highly related Src kinase.
Klebl B. et al: Protein Kinases as Drug Targets, Methods and Principles in Medicinal Chemistry, Wiley-VCH, 2011
Liu Y and Gray NS: Rationale design of inhibitors that bind to inactive kinase conformations. Nature Chemical Biology 2, 358-364, 2006
Noble MEM et al: Protein kinase inhibitors: Insight into Drug Design from Structure. Science 303, 1800-1804, 2004
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