An Irreversible Inhibitor of HSP72 that Unexpectedly Targets Lysine-56.
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Date
2017-03-20ICR Author
Author
Pettinger, J
Le Bihan, Y-V
Widya, M
van Montfort, RLM
Jones, K
Cheeseman, MD
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Collections
Research team
Medicinal Chemistry 3
Hit Discovery & Structural Design
Language
eng
Date accepted
2017-02-03
License start date
2017-03
Citation
Angewandte Chemie (International ed. in English), 2017, 56 (13), pp. 3536 - 3540
Publisher
WILEY-V C H VERLAG GMBH