The alkyne moiety as a latent electrophile in irreversible covalent small molecule inhibitors of Cathepsin K

E. Mons; I.D.C. Jansen; J. Loboda; B.R. van Doodewaerd; J. Hermans; M. Verdoes; C.A.A. van Boeckel; P.A. van Veelen; B. Turk; D. Turk; H. Ovaa

doi:10.1021/jacs.8b11027

The alkyne moiety as a latent electrophile in irreversible covalent small molecule inhibitors of Cathepsin K

E. Mons, I.D.C. Jansen, J. Loboda, B.R. van Doodewaerd, J. Hermans, M. Verdoes, C.A.A. van Boeckel, P.A. van Veelen, B. Turk, D. Turk, H. Ovaa

Periodontology

Research output: Contribution to Journal › Article › Academic › peer-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 (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.

Original language	English
Pages (from-to)	3507-3514
Journal	Journal of the American Chemical Society
Volume	141
Issue number	8
DOIs	https://doi.org/10.1021/jacs.8b11027
Publication status	Published - 27 Feb 2019

Funding

We thank Patrick Celie at The Netherlands Cancer Institute (NKI) protein facility for the expression and purification of pro-CatK and Stephanie Hoppe from the NKI for the gift of ibrutinib and afatinib. This work was supported by a VICI grant from The Netherlands Organization for Scientific Research N.W.O. (H.O.) and by P1-0140 (B.T.) and P1-0048 (D.T.) grants from Slovene Research Agency.

Funders	Funder number
NKI
Netherlands Cancer Institute
Netherlands Organization for Scientific Research N.W.O.	P1-0048, P1-0140
Slovene Research Agency
Javna Agencija za Raziskovalno Dejavnost RS

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https://hdl.handle.net/11245.1/c6648de6-11fb-4e6e-b618-732d075f73d1

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Mons, E., Jansen, I. D. C., Loboda, J., van Doodewaerd, B. R., Hermans, J., Verdoes, M., van Boeckel, C. A. A., van Veelen, P. A., Turk, B., Turk, D., & 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, 141(8), 3507-3514. https://doi.org/10.1021/jacs.8b11027

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AU - Hermans, J.

AU - Verdoes, M.

AU - van Boeckel, C.A.A.

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AU - Turk, B.

AU - Turk, D.

AU - Ovaa, H.

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The alkyne moiety as a latent electrophile in irreversible covalent small molecule inhibitors of Cathepsin K

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