As noted above, one of the first indications that the acquisition of effective peptide-based inhibitors for protein kinases might be problematic was the replacement of the phosphorylatable serine residue in the PKA substrate kemptide with an alanine to create a dead-end inhibitor. The latter proved to be an unexpectedly weak inhibitory agent (Ki>300 |iM versus the Km for kemptide <20 |iM). One of the explanations offered for the low affinity, namely loss of the hydroxyl serine side chain as a potential hydrogen bond donor, was subsequently shown to be incorrect. However, this notion does suggest that there may be ways to improve upon the use of alanine as a non-phosphorylatable replacement for serine.
Coward and his colleagues were the first to suggest that the phosphorylat-able residue in an active site-directed peptide could be substituted with an analog that is able to also engage the ATP-binding site (i.e., a bisubstrate inhibitor) (Lashmet et al. 1983).
Although the ATP-g-Ala-Ser ester 7 does not possess the requisite peptide framework for it to serve as a protein kinase inhibitor, it is a model of the type of compounds that were eventually prepared more than a decade later.
Gibson and his colleagues were the first to report the synthesis of adenosine phosphopeptides in a solid phase format (Medzihradszky et al. 1994).
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