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Literature summary for 3.4.22.38 extracted from

  • 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 (2019), J. Am. Chem. Soc., 141, 3507-3514 .
    View publication on PubMedView publication on EuropePMC
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Crystallization (Commentary)

Crystallization (Comment) Organism
-
 Homo sapiens

Inhibitors

Inhibitors Comment Organism Structure
4-fluoro-N-prop-2-yn-1-yl-N2-[(1S)-2,2,2-trifluoro-1-[4'-(methanesulfonyl)[1,1'-biphenyl]-4-yl]ethyl]-L-leucinamide
-
 Homo sapiens
E-64
-
 Homo sapiens
additional information irreversible covalent inhibitors can have a beneficial pharmacokinetic/pharmacodynamics profile but are still often avoided due to the risk of indiscriminate ovalent 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. Binding mode of alkynes is irreversible and covalent Homo sapiens
N-(1-ethynylcyclopropyl)-4-fluoro-N2-[(1S)-2,2,2-trifluoro-1-[4'-(methanesulfonyl)[1,1'-biphenyl]-4-yl]ethyl]-L-leucinamide
-
 Homo sapiens
N-(3-bromoprop-2-yn-1-yl)-4-fluoro-N2-[(1S)-2,2,2-trifluoro-1-[4'-(methanesulfonyl)[1,1'-biphenyl]-4-yl]ethyl]-L-leucinamide
-
 Homo sapiens
N-(cyanomethyl)-4-fluoro-N2-[(1S)-2,2,2-trifluoro-1-[4'-(methanesulfonyl)[1,1'-biphenyl]-4-yl]ethyl]-L-leucinamide
-
 Homo sapiens
N-but-3-yn-2-yl-4-fluoro-N2-[(1S)-2,2,2-trifluoro-1-[4'-(methanesulfonyl)[1,1'-biphenyl]-4-yl]ethyl]-L-leucinamide
-
 Homo sapiens
odanacatib
-
 Homo sapiens

Organism

Organism UniProt Comment Textmining
Homo sapiens P43235
-
-

Purification (Commentary)

Purification (Comment) Organism
-
 Homo sapiens

Source Tissue

Source Tissue Comment Organism Textmining
osteoclast
-
 Homo sapiens
-

Substrates and Products (Substrate)

Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
benzyloxycarbonyl-Phe-Arg-7-amido-4-methylcoumarin + H2O
-
 Homo sapiens benzyloxycarbonyl-Phe-Arg + 7-amino-4-methylcoumarin
-
 ?

IC50 Value

IC50 Value IC50 Value Maximum Comment Organism Inhibitor Structure
0.00000056
-
 50 mM MES pH 5.5, 25 mM EDTA and 2.5 mM DTT. 0.05% Tween20 (v/v), 37°C Homo sapiens odanacatib
0.00000057
-
 50 mM MES pH 5.5, 25 mM EDTA and 2.5 mM DTT. 0.05% Tween20 (v/v), 37°C Homo sapiens N-(cyanomethyl)-4-fluoro-N2-[(1S)-2,2,2-trifluoro-1-[4'-(methanesulfonyl)[1,1'-biphenyl]-4-yl]ethyl]-L-leucinamide
0.0000019
-
 pH and temperature not specified in the publication Homo sapiens E-64
0.000047
-
 50 mM MES pH 5.5, 25 mM EDTA and 2.5 mM DTT. 0.05% Tween20 (v/v), 37°C Homo sapiens N-(3-bromoprop-2-yn-1-yl)-4-fluoro-N2-[(1S)-2,2,2-trifluoro-1-[4'-(methanesulfonyl)[1,1'-biphenyl]-4-yl]ethyl]-L-leucinamide
0.00029
-
 50 mM MES pH 5.5, 25 mM EDTA and 2.5 mM DTT. 0.05% Tween20 (v/v), 37°C Homo sapiens 4-fluoro-N-prop-2-yn-1-yl-N2-[(1S)-2,2,2-trifluoro-1-[4'-(methanesulfonyl)[1,1'-biphenyl]-4-yl]ethyl]-L-leucinamide
0.00035
-
 50 mM MES pH 5.5, 25 mM EDTA and 2.5 mM DTT. 0.05% Tween20 (v/v), 37°C Homo sapiens N-but-3-yn-2-yl-4-fluoro-N2-[(1S)-2,2,2-trifluoro-1-[4'-(methanesulfonyl)[1,1'-biphenyl]-4-yl]ethyl]-L-leucinamide
0.026
-
 50 mM MES pH 5.5, 25 mM EDTA and 2.5 mM DTT. 0.05% Tween20 (v/v), 37°C Homo sapiens N-(1-ethynylcyclopropyl)-4-fluoro-N2-[(1S)-2,2,2-trifluoro-1-[4'-(methanesulfonyl)[1,1'-biphenyl]-4-yl]ethyl]-L-leucinamide