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Identification of Novel Proteasome Inhibitors from an Enaminone Library
Author(s) -
Elliott Megan L.,
Thomas Kevin,
Kennedy Steven,
Koduri Naga D.,
Hussaini R. Syed,
Sheaff Robert J.
Publication year - 2015
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.12496
Subject(s) - proteasome , protease , luciferase , biochemistry , chemistry , small molecule , lactacystin , viability assay , proteolysis , trypsin , enzyme , in vitro , proteasome inhibitor , transfection , gene
A library of structurally distinct enaminones was synthesized using sonication or Ru(II) catalysis to couple primary, secondary, and tertiary thioamides with α‐halocarbonyls or α‐diazocarbonyls. Screening the library for proteasome inhibition using a luciferase‐based assay identified seven structurally diverse compounds. Two of these molecules targeted luciferase, while the remaining five exhibited varying potency and specificity for the trypsin‐like, chymotrypsin‐like, or caspase‐like protease activities of the proteasome. Physiological relevance was confirmed by showing these molecules inhibited proteasomal degradation of the full‐length protein substrate p21cip1 expressed in tissue culture cells. A cell viability analysis revealed that the proteasome inhibitors differentially affected cell survival. Results indicate a subset of enaminones and precursor molecules identified in this study are good candidates for further development into novel proteasome inhibitors with potential therapeutic value.