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Correlation of High-Throughput Pregnane X Receptor (PXR) Transactivation and Binding Assays

Bristol-Myers Squibb Company, Wallingford, CTzhengrong.zhu{at}bms.com

Sean Kim

Taosheng Chen

Bristol-Myers Squibb Company, Wallingford, CT

Jun-Hsiang Lin

Aneka Bell

James Bryson

Bristol-Myers Squibb Company, Lawrenceville, NJ

Yves Dubaquie

Bristol-Myers Squibb Company, Hopewell, NJ

Ning Yan

Joseph Yanchunas

Dianlin Xie

Bristol-Myers Squibb Company, Lawrenceville, NJ

Robert Stoffel

Bristol-Myers Squibb Company, Hopewell, NJ

Michael Sinz

Kenneth Dickinson

Bristol-Myers Squibb Company, Wallingford, CT

Pregnane X receptor (PXR) transactivation and binding assays have been developed into high-throughput assays, which are robust and reproducible (Z' > 0.5). For most compounds, there was a good correlation between the results of the transactivation and binding assays. EC₅₀ values of compounds in the transactivation assay correlated reasonably well with their IC₅₀ values in the binding assay. However, there were discrepancies with some compounds showing high binding affinity in the binding assay translated into low transactivation. The most likely cause for these discrepancies was an agonist-dependent relationship between binding affinity and transactivation response. In general, compounds that bound to human PXR and transactivated PXR tended to be large hydrophobic molecules.

Key Words: PXR • transactivation assay • binding assay • HTS

Journal of Biomolecular Screening, Vol. 9, No. 6, 533-540 (2004)
DOI: 10.1177/1087057104264902


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