Development of pyrazolo[1,5-a]pyrimidine based macrocyclic
kinase inhibitors targeting AAK1

J 2025

Development of pyrazolo[1,5-a]pyrimidine based macrocyclic kinase inhibitors targeting AAK1

MENSING, Theresa E; Christian G KURZ; Jennifer A AMRHEIN; Theresa A L EHRET; Franziska PREUSS et al.

Základní údaje

Originální název

Development of pyrazolo[1,5-a]pyrimidine based macrocyclic kinase inhibitors targeting AAK1

Autoři

Vydání

European Journal of Medicinal Chemistry, ISSY-LES-MOULINEAUX, Elsevier, 2025, 0223-5234

Další údaje

Jazyk

angličtina

Typ výsledku

Článek v odborném periodiku

Obor

30104 Pharmacology and pharmacy

Stát vydavatele

Francie

Utajení

není předmětem státního či obchodního tajemství

Odkazy

URL

Impakt faktor

Impact factor: 5.900 v roce 2024

Označené pro přenos do RIV

Ano

Kód RIV

RIV/00216224:14110/25:00142462

Organizační jednotka

Lékařská fakulta

Klíčová slova anglicky

AAK1; BIKE; Kinase inhibitors; Macrocycles; Antiviral; NAK

Štítky

14110517, rivok

Příznaky

Mezinárodní význam, Recenzováno

Změněno: 5. 11. 2025 12:27, Mgr. Tereza Miškechová

Anotace

V originále

Since the outbreak of SARS-CoV-2 in recent years, our society has become more aware that zoonotic diseases pose a real threat. Therefore, the demand for small molecules that target host proteins, essential for viral entry and replication, has increased as an interesting strategy for the development of antiviral agents, as these agents may be effective against several different pathogens. NAK kinases is one such potential target family because they are involved in a variety of cellular functions, hijacked by viruses to invade host cells, such as clathrin-mediated endocytosis. A large number of different inhibitors have already been reported targeting NAK kinases, but there are still no compounds that selectively target AAK1 over other NAK family members, in particular the closely related family member BIKE. Here, we developed a series of pyrazolo[1,5-a]pyrimidine-based macrocyclic NAK inhibitors, starting from the acyclic AAK1 inhibitor LP-935509. Through a structure-guided activity relationship study within the NAK family, we identified potent AAK1 inhibitors 16, 18 and 27, which show promising selectivity within the NAK family. The inhibitors showed a potent inhibition of the phosphorylation of the AP-2 complex and the antiviral activity of the compounds was evaluated against various RNA viruses.

Citovat

MENSING, Theresa E; Christian G KURZ; Jennifer A AMRHEIN; Theresa A L EHRET; Franziska PREUSS; Sebastian MATHEA; Marwah KARIM; Do Hoang Nhu TRAN; Zuzana KADLECOVÁ; Tuomas A TOLVANEN; Daniel MARTINEZ-MOLINA; Susanne MUELLER; Shirit EINAV; Stefan KNAPP a Thomas HANKE. Development of pyrazolo[1,5-a]pyrimidine based macrocyclic kinase inhibitors targeting AAK1. European Journal of Medicinal Chemistry. ISSY-LES-MOULINEAUX: Elsevier, 2025, roč. 299, December 2025, s. 1-16. ISSN 0223-5234. Dostupné z: https://doi.org/10.1016/j.ejmech.2025.118076.

@article{2530819,
   author = {Mensing, Theresa E and Kurz, Christian G and Amrhein, Jennifer A and Ehret, Theresa A L and Preuss, Franziska and Mathea, Sebastian and Karim, Marwah and Tran, Do Hoang Nhu and Kadlecová, Zuzana and Tolvanen, Tuomas A and MartinezandMolina, Daniel and Mueller, Susanne and Einav, Shirit and Knapp, Stefan and Hanke, Thomas},
   article_location = {ISSY-LES-MOULINEAUX},
   article_number = {December 2025},
   doi = {https://doi.org/10.1016/j.ejmech.2025.118076},
   keywords = {AAK1; BIKE; Kinase inhibitors; Macrocycles; Antiviral; NAK},
   language = {eng},
   issn = {0223-5234},
   journal = {European Journal of Medicinal Chemistry},
   title = {Development of pyrazolo[1,5-a]pyrimidine based macrocyclic kinase inhibitors targeting AAK1},
   url = {https://www.sciencedirect.com/science/article/pii/S0223523425008414?pes=vor&utm_source=clarivate&getft_integrator=clarivate},
   volume = {299},
   year = {2025}
}

TY  - JOUR
ID  - 2530819
AU  - Mensing, Theresa E - Kurz, Christian G - Amrhein, Jennifer A - Ehret, Theresa A L - Preuss, Franziska - Mathea, Sebastian - Karim, Marwah - Tran, Do Hoang Nhu - Kadlecová, Zuzana - Tolvanen, Tuomas A - Martinez-Molina, Daniel - Mueller, Susanne - Einav, Shirit - Knapp, Stefan - Hanke, Thomas
PY  - 2025
TI  - Development of pyrazolo[1,5-a]pyrimidine based macrocyclic kinase inhibitors targeting AAK1
JF  - European Journal of Medicinal Chemistry
VL  - 299
IS  - December 2025
SP  - 1-16
EP  - 1-16
PB  - Elsevier
SN  - 02235234
KW  - AAK1
KW  - BIKE
KW  - Kinase inhibitors
KW  - Macrocycles
KW  - Antiviral
KW  - NAK
UR  - https://www.sciencedirect.com/science/article/pii/S0223523425008414?pes=vor&utm_source=clarivate&getft_integrator=clarivate
N2  - Since the outbreak of SARS-CoV-2 in recent years, our society has become more aware that zoonotic diseases pose a real threat. Therefore, the demand for small molecules that target host proteins, essential for viral entry and replication, has increased as an interesting strategy for the development of antiviral agents, as these agents may be effective against several different pathogens. NAK kinases is one such potential target family because they are involved in a variety of cellular functions, hijacked by viruses to invade host cells, such as clathrin-mediated endocytosis. A large number of different inhibitors have already been reported targeting NAK kinases, but there are still no compounds that selectively target AAK1 over other NAK family members, in particular the closely related family member BIKE. Here, we developed a series of pyrazolo[1,5-a]pyrimidine-based macrocyclic NAK inhibitors, starting from the acyclic AAK1 inhibitor LP-935509. Through a structure-guided activity relationship study within the NAK family, we identified potent AAK1 inhibitors 16, 18 and 27, which show promising selectivity within the NAK family. The inhibitors showed a potent inhibition of the phosphorylation of the AP-2 complex and the antiviral activity of the compounds was evaluated against various RNA viruses.
ER  -

MENSING, Theresa E; Christian G KURZ; Jennifer A AMRHEIN; Theresa A L EHRET; Franziska PREUSS; Sebastian MATHEA; Marwah KARIM; Do Hoang Nhu TRAN; Zuzana KADLECOVÁ; Tuomas A TOLVANEN; Daniel MARTINEZ-MOLINA; Susanne MUELLER; Shirit EINAV; Stefan KNAPP a Thomas HANKE. Development of pyrazolo[1,5-a]pyrimidine based macrocyclic kinase inhibitors targeting AAK1. \textit{European Journal of Medicinal Chemistry}. ISSY-LES-MOULINEAUX: Elsevier, 2025, roč.~299, December 2025, s.~1-16. ISSN~0223-5234. Dostupné z: https://doi.org/10.1016/j.ejmech.2025.118076.

Přehled o publikaci