7LVH
CRYSTAL STRUCTURE OF AP2 ASSOCIATED KINASE 1 ISOFORM 1 COMPLEXED WITH LIGAND N-[3-METHOXY-4-(1,3-OXAZOL-5-YL)PHENYL]-3-(PROPAN-2-YL)PIPERIDINE-2-CARBOXAMIDE
Summary for 7LVH
Entry DOI | 10.2210/pdb7lvh/pdb |
Descriptor | AP2-associated protein kinase 1, N-[3-methoxy-4-(1,3-oxazol-5-yl)phenyl]-D-leucinamide, 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 | 72900.51 |
Authors | Muckelbauer, J.K. (deposition date: 2021-02-25, release date: 2021-07-28, Last modification date: 2024-04-03) |
Primary citation | Hartz, R.A.,Ahuja, V.T.,Nara, S.J.,Kumar, C.M.V.,Brown, J.M.,Bristow, L.J.,Rajamani, R.,Muckelbauer, J.K.,Camac, D.,Kiefer, S.E.,Hunihan, L.,Gulianello, M.,Lewis, M.,Easton, A.,Lippy, J.S.,Surti, N.,Pattipati, S.N.,Dokania, M.,Elavazhagan, S.,Dandapani, K.,Hamman, B.D.,Allen, J.,Kostich, W.,Bronson, J.J.,Macor, J.E.,Dzierba, C.D. Discovery, Structure-Activity Relationships, and In Vivo Evaluation of Novel Aryl Amides as Brain Penetrant Adaptor Protein 2-Associated Kinase 1 (AAK1) Inhibitors for the Treatment of Neuropathic Pain. J.Med.Chem., 64:11090-11128, 2021 Cited by PubMed Abstract: Effective treatment of chronic pain, in particular neuropathic pain, without the side effects that often accompany currently available treatment options is an area of significant unmet medical need. A phenotypic screen of mouse gene knockouts led to the discovery that adaptor protein 2-associated kinase 1 (AAK1) is a potential therapeutic target for neuropathic pain. The synthesis and optimization of structure-activity relationships of a series of aryl amide-based AAK1 inhibitors led to the identification of , a brain penetrant, AAK1-selective inhibitor that proved to be a valuable tool compound. Compound was evaluated in mice for the inhibition of μ2 phosphorylation. Studies conducted with in pain models demonstrated that this compound was efficacious in the phase II formalin model for persistent pain and the chronic-constriction-injury-induced model for neuropathic pain in rats. These results suggest that AAK1 inhibition is a promising approach for the treatment of neuropathic pain. PubMed: 34270254DOI: 10.1021/acs.jmedchem.1c00472 PDB entries with the same primary citation |
Experimental method | X-RAY DIFFRACTION (2.65 Å) |
Structure validation
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