2. Academic Validation
  3. Potent and selective nonpeptide inhibitors of caspases 3 and 7

Potent and selective nonpeptide inhibitors of caspases 3 and 7

  • J Med Chem. 2001 Jun 7;44(12):2015-26. doi: 10.1021/jm0100537.
D Lee 1,  S A Long,  J H Murray,  J L Adams,  M E Nuttall,  D P Nadeau,  K Kikly,  J D Winkler,  C M Sung,  M D Ryan,  M A Levy,  P M Keller,  W E DeWolf Jr
Affiliations

Affiliation

  • 1 Department of Medicinal Chemistry, GlaxoSmithKline Pharmaceuticals, King of Prussia, Pennsylvania 19406, USA. denlee@sunesis-pharma.com
PMID: 11384246 DOI: 10.1021/jm0100537
Abstract

5-Dialkylaminosulfonylisatins have been identified as potent, nonpeptide inhibitors of caspases 3 and 7. The most active compound within this series (34) inhibited caspases 3 and 7 in the 2-6 nM range and exhibited approximately 1000-fold selectivity for caspases 3 and 7 versus a panel of five Other caspases (1, 2, 4, 6, and 8) and was at least 20-fold more selective versus Caspase 9. Sequence alignments of the active site residues of the caspases strongly suggest that the basis of this selectivity is due to binding in the S2 subsite comprised of residues Tyr204, Trp206, and Phe256 which are unique to caspases 3 and 7. These compounds inhibit Apoptosis in three cell-based models: human Jurkat T cells, human chondrocytes, and mouse bone marrow neutrophils.

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