title: Structure-activity relationship studies of QS11, a small molecule Wnt synergistic agonist.
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.
authors.affiliation: Division of Chemical Biology and Medicinal Chemistry, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Manish K
authors.initials: MK
authors.lastname: Singh
authors.affiliation: Division of Chemical Biology and Medicinal Chemistry, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Huanyao
authors.initials: H
authors.lastname: Gao
authors.affiliation: Division of Chemical Biology and Medicinal Chemistry, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Sun
authors.affiliation: Division of Chemical Biology and Medicinal Chemistry, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Zhiquan
authors.initials: Z
authors.lastname: Song
authors.affiliation: Division of Gastroenterology, School of Medicine, Duke University, Durham, NC 27710, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Schmalzigaug
authors.affiliation: Division of Gastroenterology, School of Medicine, Duke University, Durham, NC 27710, USA.
authors.forename: Richard T
authors.initials: RT
authors.lastname: Premont
authors.affiliation: Division of Chemical Biology and Medicinal Chemistry, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Electronic address: qszhang@unc.edu.
authors.forename: Qisheng
authors.initials: Q
authors.lastname: Zhang
mesh_terms: D004305:Dose-Response Relationship, Drug; D020690:GTPase-Activating Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D015394:Molecular Structure; D011687:Purines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D051153:Wnt Proteins / Q000819:agonists*; D060449:Wnt Signaling Pathway / Q000187:drug effects*; D051176:beta Catenin / Q000378:metabolism
chemical_list: C503237:ARFGAP1 protein, human; D020690:GTPase-Activating Proteins; D011687:Purines; C520339:QS11 compound; D051153:Wnt Proteins; D051176:beta Catenin
keywords: ADP-ribosylation factors; GTPase-activating proteins; QS11; Structure–activity relationship (SAR); Wnt/β-catenin signaling