7TEU
Crystal structure of JAK2 JH1 with type II inhibitor YLIU-04-105-1
Summary for 7TEU
| Entry DOI | 10.2210/pdb7teu/pdb |
| Descriptor | Tyrosine-protein kinase JAK2, 3-{(4S)-2-[(cyclopropanecarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}-N-{3-[(4-ethylpiperazin-1-yl)methyl]-5-(trifluoromethyl)phenyl}-4-methylbenzamide, GLYCEROL, ... (4 entities in total) |
| Functional Keywords | jak2, tyrosine kinase, inhibitor, cytokine signaling, transferase, transferase-inhibitor complex, transferase/inhibitor |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 37788.09 |
| Authors | Hubbard, S.R. (deposition date: 2022-01-05, release date: 2023-06-21, Last modification date: 2023-10-25) |
| Primary citation | Arwood, M.L.,Liu, Y.,Harkins, S.K.,Weinstock, D.M.,Yang, L.,Stevenson, K.E.,Plana, O.D.,Dong, J.,Cirka, H.,Jones, K.L.,Virtanen, A.T.,Gupta, D.G.,Ceas, A.,Lawney, B.,Yoda, A.,Leahy, C.,Hao, M.,He, Z.,Choi, H.G.,Wang, Y.,Silvennoinen, O.,Hubbard, S.R.,Zhang, T.,Gray, N.S.,Li, L.S. New scaffolds for type II JAK2 inhibitors overcome the acquired G993A resistance mutation. Cell Chem Biol, 30:618-, 2023 Cited by PubMed Abstract: Recurrent JAK2 alterations are observed in myeloproliferative neoplasms, B-cell acute lymphoblastic leukemia, and other hematologic malignancies. Currently available type I JAK2 inhibitors have limited activity in these diseases. Preclinical data support the improved efficacy of type II JAK2 inhibitors, which lock the kinase in the inactive conformation. By screening small molecule libraries, we identified a lead compound with JAK2 selectivity. We highlight analogs with on-target biochemical and cellular activity and demonstrate in vivo activity using a mouse model of polycythemia vera. We present a co-crystal structure that confirms the type II binding mode of our compounds with the "DFG-out" conformation of the JAK2 activation loop. Finally, we identify a JAK2 G993A mutation that confers resistance to the type II JAK2 inhibitor CHZ868 but not to our analogs. These data provide a template for identifying novel type II kinase inhibitors and inform further development of agents targeting JAK2 that overcome resistance. PubMed: 37290440DOI: 10.1016/j.chembiol.2023.05.007 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.45 Å) |
Structure validation
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