Discovery of 1-[4-(N-benzylamino)phenyl]-3-phenylurea derivatives as non-peptidic selective SUMO-sentrin specific protease (SENP)1 inhibitors

Bioorg Med Chem Lett. 2012 Aug 15;22(16):5169-73. doi: 10.1016/j.bmcl.2012.06.084. Epub 2012 Jul 3.

Abstract

We developed 1-[4-(N-benzylamino)phenyl]-3-phenylurea derivative 4 (GN6958) as a non-peptidic selective SUMO-sentrin specific protease (SENP)1 protease inhibitor based on the hypoxia inducible factor (HIF)-1α inhibitor 1 (GN6767). The direct interaction of compound 1 with SENP1 protein in cells was observed by the pull-down experiments using the biotin-tagged compound 2 coated on the streptavidin affinity column. Among the various 1-[4-(N-benzylamino)phenyl]-3-phenylurea derivatives tested, compounds 3 and 4 suppressed HIF-1α accumulation in a concentration-dependent manner without affecting the expression level of tubulin protein in HeLa cells. Both compounds inhibited SENP1 protease activity in a concentration-dependent manner, and compound 4 exhibited more potent inhibition than compound 3. Compound 4 exhibited selective inhibition against SENP1 protease activity without inhibiting other protease enzyme activities in vitro.

MeSH terms

  • Cysteine Endopeptidases
  • Drug Evaluation, Preclinical
  • Endopeptidases / chemistry*
  • Endopeptidases / metabolism
  • HeLa Cells
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / antagonists & inhibitors
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Phenylurea Compounds / chemical synthesis
  • Phenylurea Compounds / chemistry*
  • Phenylurea Compounds / metabolism
  • Protease Inhibitors / chemical synthesis
  • Protease Inhibitors / chemistry*
  • Protease Inhibitors / metabolism
  • Protein Binding
  • Tubulin / metabolism

Substances

  • GN6958
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Phenylurea Compounds
  • Protease Inhibitors
  • Tubulin
  • Endopeptidases
  • SENP1 protein, human
  • Cysteine Endopeptidases