6QBS

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

6QBS の概要

• エントリーDOI: 10.2210/pdb6qbs/pdb
• 分子名称: 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)
• 機能のキーワード: covalent inhibitor, cathepsin k, hydrolase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 48123.06

構造登録者

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. (登録日: 2018-12-21, 公開日: 2019-02-06, 最終更新日: 2024-10-09)

主引用文献

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

実験手法

X-RAY DIFFRACTION (1.7 Å)