Exploiting Atropisomerism to Increase the Target Selectivity of Kinase Inhibitors. (14th August 2015)

• Record Type: Journal Article
• Authors: Smith, Davis E.; Marquez, Isaac; Lokensgard, Melissa E.; Rheingold, Arnold L.; Hecht, David A.; Gustafson, Jeffrey L.
• Is Part Of: Angewandte Chemie. Volume 127:Number 40(2015)
• Page Start: 11920
• Page End: 11925
• Publication Date: 2015-08-14
• Subjects: Chemistry -- Periodicals; 540
• DOI: 10.1002/ange.201506085
• Languages: English
• ISSNs: 0044-8249

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Abstract</title> <p>Many biologically active molecules exist as rapidly interconverting atropisomeric mixtures. Whereas one atropisomer inhibits the desired target, the other can lead to off‐target effects. Herein, we study atropisomerism as a possibility to improve the selectivities of kinase inhibitors through the synthesis of conformationally stable pyrrolopyrimidines. Each atropisomer was isolated by HPLC on a chiral stationary phase and subjected to inhibitor profiling across a panel of 18 tyrosine kinases. Notably different selectivity patterns between atropisomers were observed, as well as improved selectivity compared to a rapidly interconverting parent molecule. Computational docking studies then provided insights into the structure‐based origins of these effects. This study is one of the first examples of the intentional preorganization of a promiscuous scaffold along an atropisomeric axis to increase target selectivity, and provides fundamental insights that may be applied to other atropisomeric target scaffolds.</p> </abstract>