Premium
Exploiting Atropisomerism to Increase the Target Selectivity of Kinase Inhibitors
Author(s) -
Smith Davis E.,
Marquez Isaac,
Lokensgard Melissa E.,
Rheingold Arnold L.,
Hecht David A.,
Gustafson Jeffrey L.
Publication year - 2015
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.201506085
Subject(s) - atropisomer , chemistry , selectivity , small molecule , molecule , chiral column chromatography , stereochemistry , enantiomer , combinatorial chemistry , biochemistry , organic chemistry , catalysis
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.