Discovery of novel cyclophilin A ligands using an H/D exchange- and mass spectrometry-based strategy.

Journal Article (Journal Article)

Cyclophilin A (CypA) is an overexpressed protein in lung cancer tumors and as a result is a potential therapeutic and diagnostic target. Described here is use of an H/D exchange- and a matrix assisted laser desorption/ionization (MALDI) mass spectrometry-based assay, termed single-point SUPREX (Stability of Unpurified Proteins from Rates of H/D Exchange), to screen 2 chemical libraries, including the 1280-compound LOPAC library and the 9600-compound DIVERSet library, for binding to CypA. This work represents the first application of single-point SUPREX using a pooled ligand approach, which is demonstrated here to yield screening rates as fast as 6 s/ligand. The false-positive and false-negative rates determined in the current work using a set of control samples were 0% and 9%, respectively. A false-positive rate of 20% was found in screening the actual libraries. Eight novel ligands to CypA were discovered, including 2-(α-naphthoyl)ethyltrimethyl-ammonium iodide, (E)-3-(4-t-Butylphenylsulfonyl)-2-propenenitrile, 3-(N-benzyl-N-isopropyl)amino-1-(naphthalen-2-yl)propan-1-one, cis-diammineplatinum (II) chloride, 1-(3,5-dichlorophenyl)-1H-pyrrole-2,5-dione, N-(3-chloro-1, 4-dioxo-1,4-dihydro-2-naphthalenyl)-N-cyclohexylacetamide, 1-[2-(3,4-dimethoxyphenyl)ethyl]-1H-pyrrole-2,5-dione, and 4-(2-methoxy-4-nitrophenyl)-1-methyl-10-oxa-4-azatricyclo[,6~]dec-8-ene-3,5-dione. These compounds, which had moderate binding affinities to CypA (i.e., K(d) values in the low micromolar range), provide new molecular scaffolds that might be useful in the development of CypA-targeted diagnostic imaging or therapeutic agents for lung cancer.

Full Text

Duke Authors

Cited Authors

  • Dearmond, PD; West, GM; Anbalagan, V; Campa, MJ; Patz, EF; Fitzgerald, MC

Published Date

  • October 2010

Published In

Volume / Issue

  • 15 / 9

Start / End Page

  • 1051 - 1062

PubMed ID

  • 20855564

Pubmed Central ID

  • PMC3197229

Electronic International Standard Serial Number (EISSN)

  • 1552-454X

Digital Object Identifier (DOI)

  • 10.1177/1087057110382775


  • eng

Conference Location

  • United States