title: Optimization of a small molecule probe that restores e-cadherin expression.
abstract: E-cadherin is a ubiquitous trans-membrane protein that has important functions in cellular contacts and has been shown to play a role in the epithelial mesenchymal transition. We have previously reported the use of an HTS screen to identify compounds that are capable of restoring e-cadherin in cancer cells. Here, we report the additional medicinal chemistry optimization of these molecules, resulting in new molecules that restore e-cadherin expression at low micromolar concentrations. Further, we report preliminary pharmacokinetic data on a compound, ML327, that can be used as a probe of e-cadherin restoration.
authors: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors: John T
authors: JT
authors: Brogan
authors: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors: Sydney L
authors: SL
authors: Stoops
authors: Vanderbilt Institute of Chemical Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors: Suzanne
authors: S
authors: Brady
authors: Department of Surgery, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors: Hanbing
authors: H
authors: An
authors: Department of Surgery, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors: Connie
authors: C
authors: Weaver
authors: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Institute of Chemical Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors: J Scott
authors: JS
authors: Daniels
authors: Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Institute of Chemical Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors: R Daniel
authors: RD
authors: Beauchamp
authors: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Chemistry, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Institute of Chemical Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors: Craig W
authors: CW
authors: Lindsley
authors: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Chemistry, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Institute of Chemical Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA. Electronic address: alex.g.waterson@vanderbilt.edu.
authors: Alex G
authors: AG
authors: Waterson
mesh_terms: D000818:Animals; D015820:Cadherins / Q000096:biosynthesis*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007555:Isoxazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D015394:Molecular Structure; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D015820:Cadherins; D007555:Isoxazoles
keywords: Cancer; E-cadherin; Epithelial mesenchymal transition; Structure activity relationship