The Mechanisms and Kinetics of Protein Kinase Inhibitors

RSC Drug Discovery Series No. 19 Kinase Drug Discovery 

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The ability of some Cr(III) complexes to activate ATP dependent kinases (496, 497) may seem surprising, as stable Cr -ATP complexes (such as XIV in Chart 2 one of the many possible stereoisomers is shown) (629) are well known to act as kinase inhibitors. Chromium(III) in these complexes is a kinetically inert replacement of a natural ATP binding ion, Mg(II) (629-631). However, a Cr(III) complex, [Cr(NH3)5(OH)] +, has recently been shown to promote the in vitro phosphorylation by ATP of the hydroxo groups of Ser and Thr residues in bovine serum albumin at pH 7.4, while several other Cr(III) complexes with N- and O-donor ligands did not possess such activity (632). The proposed phosphorylation mechanism (Scheme 12) (632) involves the formation of a ternary complex of Cr(III), ATP, and the amino acid residue. This mechanism may be related to the kinase-catalyzed phosphorylation of protein Tyr residues. 

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