Targeting Large Kinase Active Site with Rigid Bulky Octahedral Ruthenium Complexes

摘要

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 Λ->FL172 and Λ->FL411 in which the cyclopentadienyl moiety of >NP309 is replaced by a chloride and sterically demanding diimine ligands. A 1.65 Å cocrystal structure of PAK1 with Λ->FL172 reveals how the large coordination sphere of the ruthenium complex matches the size of the active site and serves as a yard stick to discriminate between otherwise closely related binding sites.