5KZI
Crystal structure of human Pim-1 kinase in complex with an imidazopyridazine inhibitor.
Summary for 5KZI
| Entry DOI | 10.2210/pdb5kzi/pdb |
| Descriptor | Serine/threonine-protein kinase pim-1, ~{N}-[4-[(3~{S})-3-azanylpiperidin-1-yl]pyridin-3-yl]-2-[2,6-bis(fluoranyl)phenyl]imidazo[1,5-b]pyridazin-7-amine (3 entities in total) |
| Functional Keywords | transferase, serine/threonine protein kinase, transferase-transferase inhibitor complex, transferase/transferase inhibitor |
| Biological source | Homo sapiens (Human) |
| Cellular location | Isoform 2: Cytoplasm. Isoform 1: Cell membrane: P11309 |
| Total number of polymer chains | 1 |
| Total formula weight | 33485.87 |
| Authors | Mohr, C. (deposition date: 2016-07-25, release date: 2016-11-09, Last modification date: 2024-03-06) |
| Primary citation | Wurz, R.P.,Sastri, C.,D'Amico, D.C.,Herberich, B.,Jackson, C.L.,Pettus, L.H.,Tasker, A.S.,Wu, B.,Guerrero, N.,Lipford, J.R.,Winston, J.T.,Yang, Y.,Wang, P.,Nguyen, Y.,Andrews, K.L.,Huang, X.,Lee, M.R.,Mohr, C.,Zhang, J.D.,Reid, D.L.,Xu, Y.,Zhou, Y.,Wang, H.L. Discovery of imidazopyridazines as potent Pim-1/2 kinase inhibitors. Bioorg. Med. Chem. Lett., 26:5580-5590, 2016 Cited by PubMed Abstract: High levels of Pim expression have been implicated in several hematopoietic and solid tumor cancers, suggesting that inhibition of Pim signaling could provide patients with therapeutic benefit. Herein, we describe our progress towards this goal using a screening hit (rac-1) as a starting point. Modification of the indazole ring resulted in the discovery of a series of imidazopyridazine-based Pim inhibitors exemplified by compound 22m, which was found to be a subnanomolar inhibitor of the Pim-1 and Pim-2 isoforms (IC values of 0.024nM and 0.095nM, respectively) and to potently inhibit the phosphorylation of BAD in a cell line that expresses high levels of all Pim isoforms, KMS-12-BM (IC=28nM). Profiling of Pim-1 and Pim-2 expression levels in a panel of multiple myeloma cell lines and correlation of these data with the potency of compound 22m in a proliferation assay suggests that Pim-2 inhibition would be advantageous for this indication. PubMed: 27769621DOI: 10.1016/j.bmcl.2016.09.067 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.1 Å) |
Structure validation
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