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Title
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Targeting large kinase active site with rigid, bulky octahedral ruthenium complexes.
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Authors
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J.Maksimoska,
L.Feng,
K.Harms,
C.Yi,
J.Kissil,
R.Marmorstein,
E.Meggers.
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Ref.
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J Am Chem Soc, 2008,
130,
15764-15765.
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PubMed id
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Abstract
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A strategy for targeting protein kinases with large ATP-binding sites by using
bulky and rigid octahedral ruthenium complexes as structural scaffolds is
presented. A highly potent and selective GSK3 and Pim1 half-sandwich complex
NP309 was successfully converted into a PAK1 inhibitor by making use of the
large octahedral compounds Lambda-FL172 and Lambda-FL411 in which the
cyclopentadienyl moiety of NP309 is replaced by a chloride and sterically
demanding diimine ligands. A 1.65 A cocrystal structure of PAK1 with
Lambda-FL172 reveals how the large coordination sphere of the ruthenium complex
matches the size of the active site and serves as a yardstick to discriminate
between otherwise closely related binding sites.
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