Synthesis and structure-activity relationship of (1-halo-2-naphthyl) carbamate-based inhibitors of KIAA1363 (NCEH1/AADACL1)

Bioorg Med Chem Lett. 2012 Sep 1;22(17):5748-51. doi: 10.1016/j.bmcl.2012.05.102. Epub 2012 Jun 6.

Abstract

KIAA1363 is a serine hydrolase whose activity has been shown to be positively associated with tumor cell invasiveness. Thus, inhibitors of KIAA1363 represent a novel targeted therapy approach towards cancer. AX11890 ((1-bromo-2-naphthyl) N,N-dimethylcarbamate) was identified as a KIAA1363 inhibitor with an IC(50) value of 1.2 μM and was shown using ESI-MS to carbamylate the catalytic residue Ser(191). SAR studies explored both substitution of the 1-bromo group and derivatization of the 6-position. Activity-based protein profiling demonstrated AX13057 inhibited tumor-localized KIAA1363 in SK-OV-3 xenograft-bearing mice.

MeSH terms

  • Animals
  • Carbamates / chemical synthesis
  • Carbamates / chemistry*
  • Carbamates / pharmacology*
  • Carbamates / therapeutic use
  • Carboxylic Ester Hydrolases / antagonists & inhibitors*
  • Carboxylic Ester Hydrolases / metabolism
  • Cell Line, Tumor
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology*
  • Enzyme Inhibitors / therapeutic use
  • Female
  • Humans
  • Mice
  • Mice, SCID
  • Ovarian Neoplasms / drug therapy
  • Ovarian Neoplasms / metabolism
  • Sterol Esterase / antagonists & inhibitors*
  • Sterol Esterase / metabolism
  • Structure-Activity Relationship

Substances

  • Carbamates
  • Enzyme Inhibitors
  • Carboxylic Ester Hydrolases
  • Nceh1 protein, mouse
  • NCEH1 protein, human
  • Sterol Esterase