Cocrystal Structures of Organometallics with Kinases

Over the last 6 years, our group developed highly potent organometallic inhibitors for the kinases GSK-3, Pim-1, MSK-1, PAK-1, and PI3K, thus demonstrating the generality of the design strategy. So far, we deposited together with our collaborators eight cocrystal structures of metal complexes with kinases in the PDB (Pim-1 with Ru: 2BZH, 2BZI, 2OI4, 2 BZJ; Pim-2 with Ru: 2IWI; PI3Kgamma with Ru: 2CST; Pim-1 with Os: 3BWF). In all these crystal structures, the metal exerts a purely structural role.

GSK-3beta with extremely tight inhibitor (PDB code 2JLD)

PAK1 with bulky octahedral ruthenium complex (PDB file to be released)

In collaboration with Ronen Marmorstein (The Wistar Institute, Philadelphia, USA). See, J. Am. Chem. Soc. 2008, 130, 15764.

Lipid kinase PI3Kgamma with E5E2 (PDB code 3CST)

Solved by Ronen Marmorstein's group (ACS Chem. Biol. 2008, 3, 305-316).

Pim1 with an Osmium Half-Sandwich Complex (PDB code 3BWF)

We replaced in this study ruthenium for its heavier homolog osmium in a bioactive half-sandwich kinase inhibitor scaffold. (Chem. Eur. J. 2008, 14, 4816-4822.).

HB1 with Pim-1 (PDB code 2BZH)

Cocrystal structure at 1.9 Å. HB1 forms two hydrogen bonds in the active site of Pim-1 in addition to typical hydrophobic interactions. The Ru-CO ligand "bumps" against the glycine rich loop. See: Angew. Chem. Int. Ed. 2006, 45, 1580.

DW2 with Pim-1 (PDB code 2BZI)

Cocrystal structure of DW2 with Pim-1 at 1.9 Å. The organometallic inhibitor occupies the ATP binding site of the kinase. This compound has an IC50 of 220 pM for Pim-1 (100 micromolar ATP). See: Angew. Chem. Int. Ed. 2006, 45, 1580.