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

John T Brogan; Sydney L Stoops; Suzanne Brady; Hanbing An; Connie Weaver; J Scott Daniels; R Daniel Beauchamp; Craig W Lindsley; Alex G Waterson

doi:10.1016/j.bmcl.2015.07.104

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. Epub 2015 Aug 6.

Authors

John T Brogan¹, Sydney L Stoops¹, Suzanne Brady², Hanbing An³, Connie Weaver³, J Scott Daniels⁴, R Daniel Beauchamp⁵, Craig W Lindsley⁶, Alex G Waterson⁷

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].

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.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Animals
Cadherins / biosynthesis*
Cell Line, Tumor
Dose-Response Relationship, Drug
Humans
Isoxazoles / chemical synthesis
Isoxazoles / chemistry
Isoxazoles / pharmacology*
Mice
Molecular Structure
Rats
Structure-Activity Relationship

Substances

Cadherins
Isoxazoles

Abstract

Publication types

MeSH terms

Substances

Grants and funding