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An Irreversible Inhibitor of HSP72 that Unexpectedly Targets Lysine‐56
Author(s) -
Pettinger Jonathan,
Le Bihan YannVaï,
Widya Marcella,
van Montfort Rob L. M.,
Jones Keith,
Cheeseman Matthew D.
Publication year - 2017
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201611907
Subject(s) - cysteine , chemistry , lysine , covalent bond , rational design , biochemistry , small molecule , cysteine metabolism , residue (chemistry) , combinatorial chemistry , enzyme , biology , amino acid , genetics , organic chemistry
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.