5EOL
Crystal structure of human Pim-1 kinase in complex with a macrocyclic quinoxaline-pyrrolodihydropiperidinone inhibitor
Summary for 5EOL
| Entry DOI | 10.2210/pdb5eol/pdb |
| Descriptor | Serine/threonine-protein kinase pim-1, macrocyclic quinoxaline-pyrrolodihydropiperidinone, GLYCEROL, ... (4 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 | 33608.03 |
| Authors | Mohr, C. (deposition date: 2015-11-10, release date: 2016-05-04, Last modification date: 2024-03-06) |
| Primary citation | Cee, V.J.,Chavez, F.,Herberich, B.,Lanman, B.A.,Pettus, L.H.,Reed, A.B.,Wu, B.,Wurz, R.P.,Andrews, K.L.,Chen, J.,Hickman, D.,Laszlo, J.,Lee, M.R.,Guerrero, N.,Mattson, B.K.,Nguyen, Y.,Mohr, C.,Rex, K.,Sastri, C.E.,Wang, P.,Wu, Q.,Wu, T.,Xu, Y.,Zhou, Y.,Winston, J.T.,Lipford, J.R.,Tasker, A.S.,Wang, H.L. Discovery and Optimization of Macrocyclic Quinoxaline-pyrrolo-dihydropiperidinones as Potent Pim-1/2 Kinase Inhibitors. Acs Med.Chem.Lett., 7:408-412, 2016 Cited by PubMed Abstract: The identification of Pim-1/2 kinase overexpression in B-cell malignancies suggests that Pim kinase inhibitors will have utility in the treatment of lymphoma, leukemia, and multiple myeloma. Starting from a moderately potent quinoxaline-dihydropyrrolopiperidinone lead, we recognized the potential for macrocyclization and developed a series of 13-membered macrocycles. The structure-activity relationships of the macrocyclic linker were systematically explored, leading to the identification of 9c as a potent, subnanomolar inhibitor of Pim-1 and -2. This molecule also potently inhibited Pim kinase activity in KMS-12-BM, a multiple myeloma cell line with relatively high endogenous levels of Pim-1/2, both in vitro (pBAD IC50 = 25 nM) and in vivo (pBAD EC50 = 30 nM, unbound), and a 100 mg/kg daily dose was found to completely arrest the growth of KMS-12-BM xenografts in mice. PubMed: 27096050DOI: 10.1021/acsmedchemlett.5b00403 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.2 Å) |
Structure validation
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