8GMD

CRYSTAL STRUCTURE OF AP2 ASSOCIATED KINASE 1 COMPLEXED WITH (5P)-3-({(8R)-5-[(4-aminopiperidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-4-yl}amino)-5-[2-(propan-2-yl)-2H-tetrazol-5-yl]phenol

Summary for 8GMD

• Entry DOI: 10.2210/pdb8gmd/pdb
• Descriptor: AP2-associated protein kinase 1, (5P)-3-({(8R)-5-[(4-aminopiperidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-4-yl}amino)-5-[2-(propan-2-yl)-2H-tetrazol-5-yl]phenol, SULFATE ION, ... (4 entities in total)
• Functional Keywords: ap2 associated kinase 1, aak1, kinase, ligand inhibitor, transferase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 73568.15

Authors

Muckelbauer, J.K. (deposition date: 2023-03-24, release date: 2023-07-12, Last modification date: 2023-10-25)

Primary citation

Dzierba, C.D.,Dasgupta, B.,Karageorge, G.,Kostich, W.,Hamman, B.,Allen, J.,Esposito, K.M.,Padmanabha, R.,Grace, J.,Lentz, K.,Morrison, J.,Morgan, D.,Easton, A.,Bourin, C.,Browning, M.R.,Rajamani, R.,Good, A.,Parker, D.D.,Muckelbauer, J.K.,Khan, J.,Camac, D.,Ghosh, K.,Halan, V.,Lippy, J.S.,Santone, K.S.,Denton, R.R.,Westphal, R.,Bristow, L.J.,Conway, C.M.,Bronson, J.J.,Macor, J.E.
Discovery of pyrrolo[2,1- f ][1,2,4]triazine-based inhibitors of adaptor protein 2-associated kinase 1 for the treatment of pain.
Med.Chem.Res., :1-7, 2023

PubMed Abstract: Adaptor protein 2-associated kinase 1 (AAK1) is a member of the Ark1/Prk1 family of serine/threonine kinases and plays a role in modulating receptor endocytosis. AAK1 was identified as a potential therapeutic target for the treatment of neuropathic pain when it was shown that AAK1 knock out (KO) mice had a normal response to the acute pain phase of the mouse formalin model, but a reduced response to the persistent pain phase. Herein we report our early work investigating a series of pyrrolo[2,1-][1,2,4]triazines as part of our efforts to recapitulate this KO phenotype with a potent, small molecule inhibitor of AAK1. The synthesis, structure-activity relationships (SAR), and in vivo evaluation of these AAK1 inhibitors is described.

PubMed: 37362320
DOI: 10.1007/s00044-023-03079-x

Experimental method

X-RAY DIFFRACTION (2.2 Å)