Identification of potent and selective TACE inhibitors via the S1 pocket

Chemical and Screening Sciences, Wyeth Research, 200 Cambridge Park Drive, Cambridge, MA 02140, USA.
Bioorganic & Medicinal Chemistry Letters (Impact Factor: 2.42). 02/2007; 17(1):34-9. DOI: 10.1016/j.bmcl.2006.10.004
Source: PubMed


By focusing on the P1 portion of the piperidine beta-sulfone ligands we identified a motif that induces selectivity and resulted in a series of TACE inhibitors that demonstrated excellent in vitro potency against isolated TACE enzyme and excellent selectivity over MMPs 1, 2, 9, 13, and 14.

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    • "as PDB entries 1BKC [11], 1ZXC [4] and 2A8H [5] respectively. In addition PDB entry 2I47 [6], where the bound ligand contains a substituted isoxazole ring at the S 2 TACE sub-site, provides a suitable protein conformation for the docking of 2E. Finally, the protein conformation in 1ZXC also proved suitable for the docking of the sulfonamide 2B. "
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