6QBS

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

Summary for 6QBS

• Entry DOI: 10.2210/pdb6qbs/pdb
• Descriptor: Cathepsin K, (2~{S})-4-methyl-~{N}-prop-2-enyl-2-[[(1~{S})-2,2,2-tris(fluoranyl)-1-[4-(4-methylsulfonylphenyl)phenyl]ethyl]amino]pentanamide, CALCIUM ION, ... (5 entities in total)
• Functional Keywords: covalent inhibitor, cathepsin k, hydrolase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 48123.06

Authors

Mons, E.,Jansen, I.D.C.,Loboda, J.,van Doodewaerd, B.R.,Verdoes, M.,van Boeckel, C.A.A.,van Veelen, P.A.,Turk, B.,Turk, D.,Hermans, J.,Ovaa, H. (deposition date: 2018-12-21, release date: 2019-02-06, Last modification date: 2024-10-09)

Primary citation

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.
The Alkyne Moiety as a Latent Electrophile in Irreversible Covalent Small Molecule Inhibitors of Cathepsin K.
J. Am. Chem. Soc., 141:3507-3514, 2019

PubMed 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) 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.

PubMed: 30689386
DOI: 10.1021/jacs.8b11027

Experimental method

X-RAY DIFFRACTION (1.7 Å)