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J Am Chem Soc. 2019 Feb 27;141(8):3507-3514. doi: 10.1021/jacs.8b11027. Epub 2019 Feb 14.

The Alkyne Moiety as a Latent Electrophile in Irreversible Covalent Small Molecule Inhibitors of Cathepsin K.

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Department of Cell and Chemical Biology, Oncode Institute , Leiden University Medical Center , 2300 RC Leiden , The Netherlands.
Division of Cell Biology , Netherlands Cancer Institute , 1066 CX Amsterdam , The Netherlands.
Department of Periodontology , Academic Center For Dentistry Amsterdam (ACTA) , 1081 LA Amsterdam , The Netherlands.
Department of Biochemistry and Molecular and Structural Biology , Jožef Stefan Institute , Ljubljana 1000 , Slovenia.
Jožef Stefan International Postgraduate School , Ljubljana 1000 , Slovenia.
Department of Tumor Immunology , Institute for Molecular Life Sciences Radboud UMC , 6525 GA Nijmegen , The Netherlands.
Leiden Institute of Chemistry , Leiden University , 2311 EZ Leiden , The Netherlands.
Centre for Proteomics and Metabolomics , Leiden University Medical Center , 2333 ZA Leiden , The Netherlands.
Faculty of Chemistry and Chemical Technology , University of Ljubljana , Ljubljana 1000 , Slovenia.
Centre of Excellence for Integrated Approaches in Chemistry and Biology of Proteins , Ljubljana 1000 , Slovenia.


Irreversible covalent inhibitors can have a beneficial pharmacokinetic/pharmacodynamics profile but are still often avoided due to the risk of indiscriminate covalent reactivity and the resulting adverse effects. To overcome this potential liability, we introduced an alkyne moiety as a latent electrophile into small molecule inhibitors of cathepsin K (CatK). Alkyne-based inhibitors do not show indiscriminate thiol reactivity but potently inhibit CatK protease activity by formation of an irreversible covalent bond with the catalytic cysteine residue, confirmed by crystal structure analysis. The rate of covalent bond formation ( kinact) does not correlate with electrophilicity of the alkyne moiety, indicative of a proximity-driven reactivity. Inhibition of CatK-mediated bone resorption is validated in human osteoclasts. Together, this work illustrates the potential of alkynes as latent electrophiles in small molecule inhibitors, enabling the development of irreversible covalent inhibitors with an improved safety profile.

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