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Irreversible Covalent Small Molecule Inhibitors of Cathepsin K

The formation of a covalent linkage between catalytic Cys25 on hCatK and the candidate drug was confirmed by solving the crystal structure of CatK–inhibitor complex on XRD2.

(Ref: Mons E. et al, JACS, 141(8), 3507-3514 (2019))


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. 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 using XRD2 structural data.

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The Alkyne Moiety as a Latent Electrophile in Irreversible Covalent Small Molecule Inhibitors of Cathepsin K,
Elma Mons, Ineke D. C. Jansen, Jure Loboda, Bjorn R. van Doodewaerd, Jill Hermans, Martijn Verdoes, Constant A. A. van Boeckel, Peter A. van Veelen, Boris Turk, Dusan Turk, and Huib Ovaa
Journal of the American Chemical Society 2019 141 (8), 3507-3514, doi: 10.1021/jacs.8b11027, PDB: 6QBS
Last Updated on Wednesday, 03 June 2020 22:54