5L4Q

Crystal Structure of Adaptor Protein 2 Associated Kinase 1 (AAK1) in Complex with LKB1 (AAK1 Dual Inhibitor)

Summary for 5L4Q

• Entry DOI: 10.2210/pdb5l4q/pdb
• Descriptor: AP2-associated protein kinase 1, ~{N}-[5-(4-cyanophenyl)-1~{H}-pyrrolo[2,3-b]pyridin-3-yl]pyridine-3-carboxamide, 1,2-ETHANEDIOL, ... (4 entities in total)
• Functional Keywords: kinase kinase domain, transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 78706.13

Authors

Sorrell, F.J.,Williams, E.,Fox, N.,Abdul Azeez, K.R.,Gileadi, O.,von Delft, F.,Edwards, A.M.,Bountra, C.,Elkins, J.M.,Knapp, S. (deposition date: 2016-05-26, release date: 2016-06-08, Last modification date: 2024-01-10)

Primary citation

Verdonck, S.,Pu, S.Y.,Sorrell, F.J.,Elkins, J.M.,Froeyen, M.,Gao, L.J.,Prugar, L.I.,Dorosky, D.E.,Brannan, J.M.,Barouch-Bentov, R.,Knapp, S.,Dye, J.M.,Herdewijn, P.,Einav, S.,De Jonghe, S.
Synthesis and Structure-Activity Relationships of 3,5-Disubstituted-pyrrolo[2,3- b]pyridines as Inhibitors of Adaptor-Associated Kinase 1 with Antiviral Activity.
J.Med.Chem., 2019

PubMed Abstract: There are currently no approved drugs for the treatment of emerging viral infections, such as dengue and Ebola. Adaptor-associated kinase 1 (AAK1) is a cellular serine-threonine protein kinase that functions as a key regulator of the clathrin-associated host adaptor proteins and regulates the intracellular trafficking of multiple unrelated RNA viruses. Moreover, AAK1 is overexpressed specifically in dengue virus-infected but not bystander cells. Because AAK1 is a promising antiviral drug target, we have embarked on an optimization campaign of a previously identified 7-azaindole analogue, yielding novel pyrrolo[2,3- b]pyridines with high AAK1 affinity. The optimized compounds demonstrate improved activity against dengue virus both in vitro and in human primary dendritic cells and the unrelated Ebola virus. These findings demonstrate that targeting cellular AAK1 may represent a promising broad-spectrum antiviral strategy.

PubMed: 31136173
DOI: 10.1021/acs.jmedchem.9b00136

Experimental method

X-RAY DIFFRACTION (1.97 Å)