Structurally Sophisticated Octahedral Metal Complexes as Highly Selective Protein Kinase Inhibitors

Abstract

The generation of synthetic compounds with exclusive target specificity is an extraordinary challenge of molecular recognition and demands novel design strategies, in particular for large and homologous protein families such as protein kinases with more than 500 members. Simple organic molecules often do not reach the necessary sophistication to fulfill this task. Here, we present six carefully tailored, stable metal-containing compounds in which unique and defined molecular geometries with natural-product-like structural complexity are constructed around octahedral ruthenium(II) or iridium(III) metal centers. Each of the six reported metal compounds displays high selectivity for an individual protein kinase, namely GSK3α, PAK1, PIM1, DAPK1, MLCK, and FLT4. Although being conventional ATP-competitive inhibitors, the combination of the unusual globular shape and rigidity characteristics, of these compounds facilitates the design of highly selective protein kinase inhibitors. Unique structural features of the octahedral coordination geometry allow novel interactions with the glycine-rich loop, which contribute significantly to binding potencies and selectivities. The sensitive correlation between metal coordination sphere and inhibition properties suggests that in this design, the metal is located at a “hot spot” with the ATP binding pocket, not too close to the hinge region where globular space is unavailable, and at the same time not too far out towards the solvent where the octahedral coordination sphere would not have a significant impact on potency and selectivity. This study thus demonstrates that inert (stable) octahedral metal complexes are sophisticated structural scaffolds for the design of highly selective chemical probes.

Metal complexes as “protein surface mimetics”

“…The use of metal co-ordination complexes as scaffolds has been pioneered by the Meggers group; they have focussed primarily on ruthenium(II) complexes, but more recently on rhodium(III), 91,92 iridium(III), 93,94 osmium(II) 95 and platinum(II) 96 coordination complexes. These have been used for inhibition of multiple protein kinases (Fig 8a) including Pim1, 97,98 glycogen synthase G"K 99 MSK1, 97 BRAF kinase, 100 and PAK1.…”

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).…”

Octahedral rhodium(III) complexes as kinase inhibitors: Control of the relative stereochemistry with acyclic tridentate ligands

“…This heterocyclic pyridocarbazole ligand was initially inspired by the natural protein kinase inhibitor staurosporine and enables the corresponding pyridocarbazole metal complexes to interact with the ATP-binding site of protein kinases [22,49]. Whereas the benzyl group of the pyridocarbazole 1a mainly serves as a crystallization handle, the tert-butyldimethylsilyl (TBS)-protected pyridocarbazole 1b was instead employed for the synthesis of bioactive rhodium complexes containing unprotected maleimide moieties that are capable of hydrogen bonding with the hinge region of the ATP binding site of kinases ( Fig.…”