| Abstract
| - The conformation of a bisindolylmaleimide may be controlled by the size of a macrocyclic ringin which it is constrained. A range of techniques were used to demonstrate that the tether controls both theratio of the two limiting conformers (syn and anti) in solution and the extent of conjugation between themaleimide and indole rings. Screening the conformationally diverse bisindolylmaleimides against a panelof protein kinases allowed their ATP binding sites to be compared using a chemical approach which, likesequence alignment, does not require detailed structural information. This approach lead to the conclusionthat several AGC group protein kinases (including PKCα, PKCβ, MSK1, p70 S6K, PDK-1, and MAPKAP-K1α) may be best inhibited by bisindolylmaleimides which adopt a compressed approximately C2-symmetricanti conformation; in constrast, GSK3β may be best inhibited by bisindolylmaleimides whose ground stateis a distorted syn conformation. It is concluded that PDK-1, whose structure has been determined by X-raycrystallography, and its mutants, may serve as particularly useful surrogates for the study of PKC inhibitors.
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