Here we report the discovery of a selective inhibitor of Aurora A, a key regulator of cell division and potential anticancer target. We used the atom category extended ligand overlap score (xLOS), a 3D ligand-based virtual screening method recently developed in our group, to select 437 shape and pharmacophore analogs of reference kinase inhibitors. Biochemical screening uncovered two inhibitor series with scaffolds unprecedented among kinase inhibitors. One of them was successfully optimized by structure-based design to a potent Aurora A inhibitor (IC50 = 2 nM) with very high kinome selectivity for Aurora kinases. This inhibitor locks Aurora A in an inactive conformation and disrupts binding to its activator protein TPX2, which impairs Aurora A localization at the mitotic spindle and induces cell division defects. This phenotype can be rescued by inhibitor-resistant Aurora A mutants. The inhibitor furthermore does not induce Aurora B specific effects in cells.

Proteases of protozoan parasites have emerged as promising targets in drug design and discovery due to their indispensable roles in the life cycles of the parasites. For the development of new therapeutic agents against the malarial parasite Plasmodium falciparum, attention has turned to a family of cysteine proteases taking part in the degradation of human haemoglobin. The falcipains have key functions in this metabolic process, making them attractive targets for the development of novel antimalarials. To inhibit the cathepsin L-like cysteine protease falcipain-2, we designed peptidomimetic nitriles through rational structure-based molecular modelling focusing on the optimal occupancy of the selectivitydetermining subpockets. A series of compounds was efficiently prepared and their biological activity assessed to explore the binding site properties of the target enzyme. Inhibitory affinities down to the single-digit micromolar range were obtained for this first generation of covalent, reversible cysteine protease inhibitors. High selectivity against human cathepsin B and L, as well as against the serine protease a-chymotrypsin was observed for the majority of the synthesised ligands. The ideal occupation of the selectivity-determining S2 pocket and the balanced electrophilicity of the nitrile group seem to be crucial to achieve both potency and selectivity.

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