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Structure-activity relationship studies of QS11, a small molecule Wnt synergistic agonist.
- Source :
-
Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2015 Nov 01; Vol. 25 (21), pp. 4838-4842. Date of Electronic Publication: 2015 Jun 23. - Publication Year :
- 2015
-
Abstract
- Both the Wnt/β-catenin signaling pathway and small GTPases of the ADP-ribosylation factors (ARF) family play important roles in regulating cell development, homeostasis and fate. The previous report of QS11, a small molecule Wnt synergist that binds to ARF GTPase-activating protein 1 (ARFGAP1), suggests a role for ARFGAP1 in the Wnt/β-catenin pathway. However, direct inhibition of enzymatic activity of ARFGAP1 by QS11 has not been established. Whether ARFGAP1 is the only target that contributes to QS11's Wnt synergy is also not clear. Here we present structure-activity relationship (SAR) studies of QS11 analogs in two assays: direct inhibition of enzymatic activity of purified ARFGAP1 protein and cellular activation of the Wnt/β-catenin pathway. The results confirm the direct inhibition of ARFGAP1 by QS11, and also suggest the presence of other potential cellular targets of QS11.<br /> (Copyright © 2015 Elsevier Ltd. All rights reserved.)
- Subjects :
- Dose-Response Relationship, Drug
GTPase-Activating Proteins metabolism
Humans
Molecular Structure
Purines chemical synthesis
Structure-Activity Relationship
beta Catenin metabolism
GTPase-Activating Proteins antagonists & inhibitors
Purines chemistry
Purines pharmacology
Wnt Proteins agonists
Wnt Signaling Pathway drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1464-3405
- Volume :
- 25
- Issue :
- 21
- Database :
- MEDLINE
- Journal :
- Bioorganic & medicinal chemistry letters
- Publication Type :
- Academic Journal
- Accession number :
- 26152429
- Full Text :
- https://doi.org/10.1016/j.bmcl.2015.06.062