Back-pocket optimization of 2-aminopyrimidine-based macrocycles leads to potent dual EPHA2/GAK kinase inhibitors with antiviral activity
Macrocyclization of acyclic compounds is a powerful strategy for improving inhibitor potency and selectivity. Here, we developed a 2-aminopyrimidine-based macrocyclic dual EPHA2/GAK kinase inhibitor as a chemical tool to study the role of these two kinases in viral entry and assembly. 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 as a potent dual EPHA2/GAK inhibitor. 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/GAK inhibitor 55 prevented dengue virus infection of Huh7 liver cells, mainly via its EPHA2 activity, and is therefore a promising candidate for further optimization of its activity against dengue virus.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - year:2024 |
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| Enthalten in: |
bioRxiv : the preprint server for biology - (2024) vom: 18. Feb. |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Gerninghaus, Joshua [VerfasserIn] |
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| Anmerkungen: |
Date Revised 01.03.2024 published: Electronic Citation Status PubMed-not-MEDLINE |
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| doi: |
10.1101/2024.02.18.580805 |
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| PPN (Katalog-ID): |
NLM368958833 |
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| 100 | 1 | |a Gerninghaus, Joshua |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Back-pocket optimization of 2-aminopyrimidine-based macrocycles leads to potent dual EPHA2/GAK kinase inhibitors with antiviral activity |
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| 500 | |a Date Revised 01.03.2024 | ||
| 500 | |a published: Electronic | ||
| 500 | |a Citation Status PubMed-not-MEDLINE | ||
| 520 | |a Macrocyclization of acyclic compounds is a powerful strategy for improving inhibitor potency and selectivity. Here, we developed a 2-aminopyrimidine-based macrocyclic dual EPHA2/GAK kinase inhibitor as a chemical tool to study the role of these two kinases in viral entry and assembly. 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 as a potent dual EPHA2/GAK inhibitor. 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/GAK inhibitor 55 prevented dengue virus infection of Huh7 liver cells, mainly via its EPHA2 activity, and is therefore a promising candidate for further optimization of its activity against dengue virus | ||
| 650 | 4 | |a Preprint | |
| 700 | 1 | |a Zhubi, Rezart |e verfasserin |4 aut | |
| 700 | 1 | |a Krämer, Andreas |e verfasserin |4 aut | |
| 700 | 1 | |a Karim, Marwah |e verfasserin |4 aut | |
| 700 | 1 | |a Tran, Do Hoang Nhu |e verfasserin |4 aut | |
| 700 | 1 | |a Joerger, Andreas C |e verfasserin |4 aut | |
| 700 | 1 | |a Schreiber, Christian |e verfasserin |4 aut | |
| 700 | 1 | |a Berger, Lena M |e verfasserin |4 aut | |
| 700 | 1 | |a Berger, Benedict-Tilman |e verfasserin |4 aut | |
| 700 | 1 | |a Ehret, Theresa A L |e verfasserin |4 aut | |
| 700 | 1 | |a Elson, Lewis |e verfasserin |4 aut | |
| 700 | 1 | |a Lenz, Christopher |e verfasserin |4 aut | |
| 700 | 1 | |a Saxena, Krishna |e verfasserin |4 aut | |
| 700 | 1 | |a Müller, Susanne |e verfasserin |4 aut | |
| 700 | 1 | |a Einav, Shirit |e verfasserin |4 aut | |
| 700 | 1 | |a Knapp, Stefan |e verfasserin |4 aut | |
| 700 | 1 | |a Hanke, Thomas |e verfasserin |4 aut | |
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