Kinetic Optimization of Lysine-Targeting Covalent Inhibitors of HSP72.
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Date
2019-12-26ICR Author
Author
Pettinger, J
Carter, M
Jones, K
Cheeseman, MD
Type
Journal Article
Metadata
Show full item recordAbstract
The covalent inhibition mechanism of action, which overcomes competition with high-affinity, high-abundance substrates of challenging protein targets, can deliver effective chemical probes and drugs. The success of this strategy has centered on exposed cysteine residues as nucleophiles but the low abundance of cysteine in the proteome has limited its application. We have recently reported our discovery that lysine-56 in the difficult-to-drug target HSP72 could form a covalent bond with a small-molecule inhibitor. We now disclose the optimization of these targeted covalent inhibitors using rational design. Essential to our optimization was the development of a new covalent fluorescence polarization assay, which allows for the direct measurement of the key kinetic parameter in covalent inhibitor design, kinact/KI, extrapolation of the underlying parameters, kinact and Ki, and direct comparison to reversible analogues. Using our approach, we demonstrate a >100-fold enhancement in covalent efficiency and key learnings in lysine-selective electrophile optimization.
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Subject
Humans
Lysine
Molecular Structure
Structure-Activity Relationship
Kinetics
HSP72 Heat-Shock Proteins
Small Molecule Libraries
Drug Discovery
Research team
Medicinal Chemistry 3
Language
eng
License start date
2019-12-06
Citation
Journal of medicinal chemistry, 2019, 62 (24), pp. 11383 - 11398
Publisher
AMER CHEMICAL SOC