2-Anilino-4-aryl-1,3-thiazole inhibitors of valosin-containing protein (VCP or p97)

Bioorg Med Chem Lett. 2010 Mar 1;20(5):1677-9. doi: 10.1016/j.bmcl.2010.01.058. Epub 2010 Jan 21.

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.

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