7RJ6

CRYSTAL STRUCTURE OF AP2 ASSOCIATED KINASE 1 ISOFORM 1 COMPLEXED WITH LIGAND (2R)-2-AMINO-N-[3-(DIFLUOROM ETHOXY)-4-(1,3-OXAZOL-5-YL)PHENYL]-4-METHYLPENTANAMIDE

Summary for 7RJ6

• Entry DOI: 10.2210/pdb7rj6/pdb
• Descriptor: AP2-associated protein kinase 1, 5-[(4-aminopiperidin-1-yl)methyl]-N-{3-[5-(propan-2-yl)-1,3,4-thiadiazol-2-yl]phenyl}pyrrolo[2,1-f][1,2,4]triazin-4-amine, SULFATE ION, ... (5 entities in total)
• Functional Keywords: kinase, aak1, ligand, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Mus musculus (Mouse)
• Total number of polymer chains: 2
• Total formula weight: 73291.80

Authors

Muckelbauer, J. (deposition date: 2021-07-20, release date: 2022-02-23, Last modification date: 2024-04-03)

Primary citation

Hartz, R.A.,Ahuja, V.T.,Nara, S.J.,Kumar, C.M.V.,Manepalli, R.K.V.L.P.,Sarvasiddhi, S.K.,Honkhambe, S.,Patankar, V.,Dasgupta, B.,Rajamani, R.,Muckelbauer, J.K.,Camac, D.M.,Ghosh, K.,Pokross, M.,Kiefer, S.E.,Brown, J.M.,Hunihan, L.,Gulianello, M.,Lewis, M.,Lippy, J.S.,Surti, N.,Hamman, B.D.,Allen, J.,Kostich, W.A.,Bronson, J.J.,Macor, J.E.,Dzierba, C.D.
Bicyclic Heterocyclic Replacement of an Aryl Amide Leading to Potent and Kinase-Selective Adaptor Protein 2-Associated Kinase 1 Inhibitors.
J.Med.Chem., 65:4121-4155, 2022

PubMed Abstract: Adaptor protein 2-associated kinase 1 (AAK1) is a serine/threonine kinase that was identified as a therapeutic target for the potential treatment of neuropathic pain. Inhibition of AAK1 in the central nervous system, particularly within the spinal cord, was found to be the relevant site for achieving an antinociceptive effect. We previously reported that compound is a brain-penetrant, AAK1 inhibitor that showed efficacy in animal models for neuropathic pain. One approach we took to improve upon the potency of involved tying the amide back into the neighboring phenyl ring to form a bicyclic heterocycle. Investigation of the structure-activity relationships (SARs) of substituents on the resultant quinazoline and quinoline ring systems led to the identification of , a brain-penetrant, AAK1-selective inhibitor with improved enzyme and cellular potency compared to . The synthesis, SAR, and in vivo evaluation of a series of quinazoline and quinoline-based AAK1 inhibitors are described herein.

PubMed: 35171586
DOI: 10.1021/acs.jmedchem.1c01966

Experimental method

X-RAY DIFFRACTION (2.132 Å)