Journal
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
Volume 56, Issue 13, Pages 3536-3540Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.201611907
Keywords
fluorescence polarization; irreversible inhibitors; mass spectrometry; medicinal chemistry; structural biology
Categories
Funding
- ICR Chairman's Studentship Award
- Cancer Research UK [C309/A8274, C309/A11566]
- Cancer Research UK [11566, 22897] Funding Source: researchfish
Ask authors/readers for more resources
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available