9QB5

AP2-associated protein kinase 1 (AAK1) bound to CKJB68

Summary for 9QB5

• Entry DOI: 10.2210/pdb9qb5/pdb
• Descriptor: AP2-associated protein kinase 1, ~{N}-(phenylmethyl)-7,10-dioxa-13,17,18,21-tetrazatetracyclo[12.5.2.1^{2,6}.0^{17,20}]docosa-1(20),2(22),3,5,14(21),15,18-heptaene-5-carboxamide, SULFATE ION, ... (4 entities in total)
• Functional Keywords: kinase inhibitor macrocycle, transferase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 73089.84

Authors

Preuss, F.,Mensing, T.E.,Hanke, T.,Knapp, S.,Mathea, S. (deposition date: 2025-02-28, release date: 2025-04-09, Last modification date: 2025-10-22)

Primary citation

Mensing, T.E.,Kurz, C.G.,Amrhein, J.A.,Ehret, T.A.L.,Preuss, F.,Mathea, S.,Karim, M.,Tran, D.H.N.,Kadlecova, Z.,Tolvanen, T.A.,Martinez-Molina, D.,Muller, S.,Einav, S.,Knapp, S.,Hanke, T.
Development of pyrazolo[1,5-a]pyrimidine based macrocyclic kinase inhibitors targeting AAK1.
Eur.J.Med.Chem., 299:118076-118076, 2025

PubMed Abstract: 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.

PubMed: 40882436
DOI: 10.1016/j.ejmech.2025.118076

Experimental method

X-RAY DIFFRACTION (2 Å)