Journal
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
Volume 22, Issue 16, Pages 5169-5173Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2012.06.084
Keywords
SENP1; Non-peptidic inhibitors; HIF-1; deSUMOylation; Selective inhibition
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Funding
- Grants-in-Aid for Scientific Research [24102526] Funding Source: KAKEN
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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)-1 alpha 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-1 alpha 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. (c) 2012 Elsevier Ltd. All rights reserved.
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