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

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.

• Authors: Masaharu Uno, Yosuke Koma, Hyun Seung Ban, Hiroyuki Nakamura
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 22 Issue 16 Pg. 5169-73 (Aug 15 2012) ISSN: 1464-3405 [Electronic] England
• PMID: 22801642 (Publication Type: Journal Article)
• Copyright: Copyright © 2012 Elsevier Ltd. All rights reserved.

Chemical References

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

Topics

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