Optimization of a small molecule probe that restores e-cadherin expression

  • Bioorg Med Chem Lett. 2015 Oct 1;25(19):4260-4. doi: 10.1016/j.bmcl.2015.07.104.
John T Brogan  1 ,  Sydney L Stoops  1 ,  Suzanne Brady  2 ,  Hanbing An  3 ,  Connie Weaver  3 ,  J Scott Daniels  4 ,  R Daniel Beauchamp  5 ,  Craig W Lindsley  6 ,  Alex G Waterson  7
Affiliations
  • 1. Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
  • 2. Vanderbilt Institute of Chemical Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
  • 3. Department of Surgery, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
  • 4. Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Institute of Chemical Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
  • 5. 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.
  • 6. 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.
  • 7. 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: [email protected].
PMID: 26299347 DOI: 10.1016/j.bmcl.2015.07.104
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.

Keywords
Cancer; E-cadherin; Epithelial mesenchymal transition; Structure activity relationship.