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Targeting large kinase active site with rigid, bulky octahedral ruthenium complexes.

ABSTRACT: 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.

SUBMITTER: Maksimoska J

PROVIDER: S-EPMC2654244 | biostudies-literature | 2008 Nov

REPOSITORIES: biostudies-literature

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Targeting large kinase active site with rigid, bulky octahedral ruthenium complexes.

Maksimoska Jasna J Feng Li L Harms Klaus K Yi Chunling C Kissil Joseph J Marmorstein Ronen R Meggers Eric E

Journal of the American Chemical Society 20081101 47

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 stru ...[more]

PMID: 18973295

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