11 Ac-Cys-X-Pro-Lys-Lys-NHCH3

The latter exhibits a 25-fold selectivity in favor of PKA (Ki=4 nM) versus PKC (Ki=100 nM). The inhibitory potency of this derivative is impressive when one considers the fact that the ATP mimic alone is a nearly three orders of magnitude poorer inhibitor than 10. However, since the ATP analog is appended off the N-terminus of the peptide, an unanswered question is the nature of the requisite structural requirements to replace a serine moiety that is contained within the interior of a consensus sequence. Finally, 10 acts as a competitive inhibitor versus variable ATP, but is not competitive with respect to variable peptide substrate. Sasaki, Maeda, and their coworkers likewise utilized an ATP analog (a bisindolylmaleimide) to prepare a series of bisubstrate inhibitors 11 that are designed to target the cyclin-dependent protein kinase, cdc2 (Sasaki et al. 1998). The best inhibitors display IC50 values in the low micromolar range (where X=no amino acid). However, when X=Ser, the inhibitory potency is reduced by two orders of magnitude.

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