Daniel Robinson

The discovery of the potent aurora inhibitor MK-0457 (VX-680).

The identification of a novel series of Aurora kinase inhibitors and exploitation of their SAR is described. Replacement of the initial quinazoline core with a pyrimidine scaffold and modification of substituents led to a series of very potent inhibitors of cellular proliferation. MK-0457 (VX-680) has been assessed in Phase II clinical trials in patients with treatment-refractory chronic myelogenous leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) containing the T315I mutation.

A Role for Hydration in Interleukin-2 Inducible T Cell Kinase (Itk) Selectivity.

The selectivity profile of kinase inhibitors is commonly explained in terms of favourable or unfavourable interactions between the inhibitor and active site residues. In practice residue sequence differences have not always been sufficient to explain observed selectivity profiles. A series of interleukin‐2 inducible T cell kinase (Itk, EC 2.7.10.2) inhibitors that achieve selectivity through the introduction of a single nitrogen atom in an aromatic ring has recently been discovered. Structures of these inhibitors bound to Itk showed this nitrogen to be solvent exposed and not involved in any direct interactions with the enzyme. By analysing active site hydration, using the molecular dynamics tool WaterMap, the observed selectivity profile can be explained in terms of the replacement of a thermodynamically unfavourable water molecule by the inhibitor and improved hydration of the bound ligand. The location of this hydration site was successfully used to enrich virtual screening results in their content of selective Itk inhibitors.