Tethering identifies fragment that yields potent inhibitors of human caspase-1

  • Bioorg Med Chem Lett. 2006 Feb;16(3):559-62. doi: 10.1016/j.bmcl.2005.10.048.
Bruce T Fahr  1 ,  Tom O'Brien ,  Phuongly Pham ,  Nathan D Waal ,  Subramanian Baskaran ,  Brian C Raimundo ,  Joni W Lam ,  Michelle M Sopko ,  Hans E Purkey ,  Michael J Romanowski
Affiliations
  • 1. Department of Chemistry, Sunesis Pharmaceuticals, 341 Oyster Point Boulevard, South San Francisco, CA 94080, USA. [email protected]
PMID: 16274992 DOI: 10.1016/j.bmcl.2005.10.048
Abstract

Disulfide Tethering was applied to the active site of human Caspase-1, resulting in the discovery of a novel, tricyclic molecular fragment that selectively binds in S4. This fragment was developed into a class of potent inhibitors of human Caspase-1. Several key analogues determined the optimal distance of the tricycle from the catalytic residues, the relative importance of various features of the tricycle, and the importance of the linker.

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