MEDI 355 |
| Protein kinases play essential roles in controlling and modulating signal transduction pathways in the cell. Mutations in the corresponding encoding genes can lead to upregulation of protein kinase function, and this has been observed in a large number of different types of cancer as well as in inflammation. The members of the Aurora family of protein kinases play an important role in cell division and are required for multiple aspects of mitosis. Aurora A and Aurora B are both over-expressed in a wide range of different human tumours, including breast, lung, colon, ovarian, and pancreatic cancers. Inhibition of the Aurora kinases has been shown to suppress tumour growth in vivo, and the first small-molecule inhibitors of the Aurora kinases have progressed into phase II clinical trails. Here we report on the design, synthesis, structure-activity and structure-selectivity relationships of tetrahydrobenzo[b]thiophene derivatives that were initially derived from a screening hit targeted against a mycobacterial kinase. Re-purposing by application of a Chemical Proteomics technology and systematic exploration of the core structure and its molecular periphery allowed us to establish initial structure-activity relationships. By establishing a pharmacophore model the key features for mediating the inhibitor-Aurora A interaction were elaborated. The majority of synthesized analogues led to the initial assumption that substituents linked to the 2-position of the underlying core were accommodated by the hydrophobic backpocket of Aurora A. Only with the support of protein X-ray crystallography the final binding mode of the tetrahydrobenzo[b]thiophenes in complex with Aurora A could be determined, revealing a striking contrast to the initially derived binding model. The value of high-resolution complex structures of inhibitor-kinase complexes will be highlighted together with the molecular interaction details that now provide a sound basis for any further optimization programs. |
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Poster Session
7:00 PM-9:00 PM, Wednesday, August 22, 2007 BCEC -- Exhibit Hall - B2, Poster
Division of Medicinal Chemistry |