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 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.

Metal complexes as “protein surface mimetics”

“…8b). 98,102,103 The majority of these coordination complexes function mechanistically as ATP 107 This approach has been informative in highlighting the utility of metal complexes for projecting recognition groups along vectors to gain additional non-covalent contacts with target proteins in a manner that is not possible using organic molecules.…”

P21 activated kinases

“…Pak1 shRNA inhibits cell proliferation, 142 suggesting that shRNA may be another strategy for blocking the Paks. FL172 143 and OS-2 144 are examples of kinase inhibitors with some specificity toward the group A Paks. Pfizer has developed the inhibitor, PF-3758309, which was designed specifically to block the Pak4 kinase activity, but which turned out to be broadly inhibitory toward both group A and group B Paks, and also other kinases, including AMPK (AMP-dependent kinase) and RSK (ribosomal S6 kinase).…”

Polypyridyl Metal Complexes with Biological Activity

“…As demonstrated in the case of the staurosporine analogue FL172, [22] where the Λ isomer (IC 50 = 130 nm) is a significantly better inhibitor of PAK-1 than the Δ isomer (3480 nm), asymmetric synthesis of octahedral complexes will prove valuable for the preparation of optically pure complexes of enhanced potency and selectivity.…”