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, Huib Ovaa

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

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 (k inact ) 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.
Original languageEnglish
Pages (from-to)3507-3514
JournalJournal of the American Chemical Society
Volume141
Issue number8
DOIs
Publication statusPublished - 27 Feb 2019
Externally publishedYes

Cite this

Mons, Elma ; Jansen, Ineke D. C. ; Loboda, Jure ; van Doodewaerd, Bjorn R. ; Hermans, Jill ; Verdoes, Martijn ; van Boeckel, Constant A. A. ; van Veelen, Peter A. ; Turk, Boris ; Ovaa, Huib. / The Alkyne Moiety as a Latent Electrophile in Irreversible Covalent Small Molecule Inhibitors of Cathepsin K. In: Journal of the American Chemical Society. 2019 ; Vol. 141, No. 8. pp. 3507-3514.
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abstract = "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 (k inact ) 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.",
author = "Elma Mons and Jansen, {Ineke D. C.} and Jure Loboda and {van Doodewaerd}, {Bjorn R.} and Jill Hermans and Martijn Verdoes and {van Boeckel}, {Constant A. A.} and {van Veelen}, {Peter A.} and Boris Turk and Huib Ovaa",
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Mons, E, Jansen, IDC, Loboda, J, van Doodewaerd, BR, Hermans, J, Verdoes, M, van Boeckel, CAA, van Veelen, PA, Turk, B & Ovaa, H 2019, 'The Alkyne Moiety as a Latent Electrophile in Irreversible Covalent Small Molecule Inhibitors of Cathepsin K' Journal of the American Chemical Society, vol. 141, no. 8, pp. 3507-3514. https://doi.org/10.1021/jacs.8b11027

The Alkyne Moiety as a Latent Electrophile in Irreversible Covalent Small Molecule Inhibitors of Cathepsin K. / Mons, Elma; Jansen, Ineke D. C.; Loboda, Jure; van Doodewaerd, Bjorn R.; Hermans, Jill; Verdoes, Martijn; van Boeckel, Constant A. A.; van Veelen, Peter A.; Turk, Boris; Ovaa, Huib.

In: Journal of the American Chemical Society, Vol. 141, No. 8, 27.02.2019, p. 3507-3514.

Research output: Contribution to journalArticleAcademicpeer-review

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AU - Ovaa, Huib

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