2. Academic Validation
  3. Back-Pocket Optimization of 2-Aminopyrimidine-Based Macrocycles Leads to Potent EPHA2/GAK Kinase Inhibitors

Back-Pocket Optimization of 2-Aminopyrimidine-Based Macrocycles Leads to Potent EPHA2/GAK Kinase Inhibitors

  • J Med Chem. 2024 Jul 19. doi: 10.1021/acs.jmedchem.4c00411.
Joshua Gerninghaus 1 2,  Rezart Zhubi 1 2,  Andreas Krämer 1 2,  Marwah Karim 3,  Do Hoang Nhu Tran 3,  Andreas C Joerger 1 2,  Christian Schreiber 1 2,  Lena M Berger 1 2,  Benedict-Tilman Berger 1 2,  Theresa A L Ehret 1 2,  Lewis Elson 1 2,  Christopher Lenz 1 2,  Krishna Saxena 1 2,  Susanne Müller 1 2,  Shirit Einav 3 4,  Stefan Knapp 1 2,  Thomas Hanke 1 2
Affiliations

Affiliations

  • 1 Institute of Pharmaceutical Chemistry, Goethe University, Max-von-Laue-Str. 9, Frankfurt am Main 60438, Germany.
  • 2 Structural Genomics Consortium (SGC), Buchmann Institute for Life Sciences, Max-von-Laue-Str. 15, Frankfurt am Main 60438, Germany.
  • 3 Department of Medicine, Division of Infectious Diseases and Geographic Medicine, and Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California 94305, United States.
  • 4 Chan Zuckerberg Biohub, 499 Illinois St, San Francisco, California 94158, United States.
PMID: 39028937 DOI: 10.1021/acs.jmedchem.4c00411
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 23 provided 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 cellulo selectivity profile, favoring EphA4 over the other Ephrin Receptor kinase family members. The dual EphA2/A4 and GAK inhibitor 55 prevented Dengue virus infection of Huh7 liver cells. However, further investigations are needed to determine whether this was a compound-specific effect or target-related.

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