1. Back-Pocket Optimization of 2-Aminopyrimidine-Based Macrocycles Leads to Potent EPHA2/GAK Kinase Inhibitors
- Author
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Gerninghaus, Joshua, Zhubi, Rezart, Krämer, Andreas, Karim, Marwah, Tran, Do Hoang Nhu, Joerger, Andreas C., Schreiber, Christian, Berger, Lena M., Berger, Benedict-Tilman, Ehret, Theresa A.L., Elson, Lewis, Lenz, Christopher, Saxena, Krishna, Müller, Susanne, Einav, Shirit, Knapp, Stefan, and Hanke, Thomas
- Abstract
Macrocyclization of acyclic compounds is a powerful strategy for improving inhibitor potency and selectivity. Here we have optimized 2-aminopyrimidine-based macrocycles to use these compounds as chemical tools for the ephrin kinase family. Starting with a promiscuous macrocyclic inhibitor, 6, we performed a structure-guided activity relationship and selectivity study using a panel of over 100 kinases. The crystal structure of EPHA2 in complex with the developed macrocycle 23provided a basis for further optimization by specifically targeting the back pocket, resulting in compound 55, a potent inhibitor of EPHA2/A4 and GAK. Subsequent front-pocket derivatization resulted in an interesting in celluloselectivity profile, favoring EPHA4 over the other ephrin receptor kinase family members. The dual EPHA2/A4 and GAK inhibitor 55prevented dengue virus infection of Huh7 liver cells. However, further investigations are needed to determine whether this was a compound-specific effect or target-related.
- Published
- 2024
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