Abstract
Valosin-containing protein (VCP; also known as p97) is a member of the AAA ATPase family with a central role in the ubiquitin-degradation of misfolded proteins. VCP also exhibits antiapoptotic function and metastasis via activation of nuclear factor kappa-B signaling pathway. We have discovered that 2-anilino-4-aryl-1,3-thiazoles are potent drug-like inhibitors of this enzyme. The identified compounds show low nanomolar VCP potency, demonstrate SAR trends, and show activity in a mechanism based cellular assay. This series of compounds represents the first steps towards a novel, small molecule VCP inhibitor as a cancer therapeutic.
Copyright 2010 Elsevier Ltd. All rights reserved.
MeSH terms
-
Adenosine Triphosphatases / antagonists & inhibitors*
-
Adenosine Triphosphatases / metabolism
-
Aniline Compounds / chemical synthesis
-
Aniline Compounds / chemistry*
-
Antineoplastic Agents / chemical synthesis
-
Antineoplastic Agents / chemistry*
-
Antineoplastic Agents / pharmacology
-
Cell Cycle Proteins / antagonists & inhibitors*
-
Cell Cycle Proteins / metabolism
-
HeLa Cells
-
Humans
-
NF-kappa B / metabolism
-
Signal Transduction
-
Structure-Activity Relationship
-
Thiazoles / chemical synthesis
-
Thiazoles / chemistry*
-
Thiazoles / pharmacology
-
Valosin Containing Protein
Substances
-
Aniline Compounds
-
Antineoplastic Agents
-
Cell Cycle Proteins
-
NF-kappa B
-
Thiazoles
-
Adenosine Triphosphatases
-
VCP protein, human
-
Valosin Containing Protein