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- Title
An Irreversible Inhibitor of HSP72 that Unexpectedly Targets Lysine-56.
- Authors
Pettinger, Jonathan; Le Bihan, Yann‐Vaï; Widya, Marcella; van Montfort, Rob L. M.; Jones, Keith; Cheeseman, Matthew D.
- Abstract
The stress-inducible molecular chaperone, HSP72, is an important therapeutic target in oncology, but inhibiting this protein with small molecules has proven particularly challenging. Validating HSP72 inhibitors in cells is difficult owing to competition with the high affinity and abundance of its endogenous nucleotide substrates. We hypothesized this could be overcome using a cysteine-targeted irreversible inhibitor. Using rational design, we adapted a validated 8- N-benzyladenosine ligand for covalent bond formation and confirmed targeted irreversible inhibition. However, no cysteine in the protein was modified; instead, we demonstrate that lysine-56 is the key nucleophilic residue. Targeting this lysine could lead to a new design paradigm for HSP72 chemical probes and drugs.
- Subjects
MOLECULAR chaperones; NUCLEOTIDE synthesis; LIGANDS (Chemistry); NUCLEOPHILIC reactions; CHEMICAL inhibitors
- Publication
Angewandte Chemie, 2017, Vol 129, Issue 13, p3590
- ISSN
0044-8249
- Publication type
Article
- DOI
10.1002/ange.201611907