3UMW
Crystal structure of Pim1 kinase in complex with inhibitor (Z)-2-[(1H-indazol-3-yl)methylene]-6-methoxy-7-(piperazin-1-ylmethyl)benzofuran-3(2H)-one
Summary for 3UMW
| Entry DOI | 10.2210/pdb3umw/pdb |
| Related | 3UIX 3UMX |
| Descriptor | Proto-oncogene serine/threonine-protein kinase pim-1, GLYCEROL, SULFATE ION, ... (5 entities in total) |
| Functional Keywords | pim1, kinase inhibitor, rational drug design, leukemia, transferase-inhibitor complex, transferase/inhibitor |
| Biological source | Homo sapiens |
| Cellular location | Isoform 2: Cytoplasm. Isoform 1: Cell membrane: P11309 |
| Total number of polymer chains | 1 |
| Total formula weight | 34766.32 |
| Authors | Parker, L.J.,Handa, N.,Yokoyama, S. (deposition date: 2011-11-14, release date: 2012-10-03, Last modification date: 2023-11-01) |
| Primary citation | Nakano, H.,Saito, N.,Parker, L.J.,Tada, Y.,Abe, M.,Tsuganezawa, K.,Yokoyama, S.,Tanaka, A.,Kojima, H.,Okabe, T.,Nagano, T. Rational evolution of a novel type of potent and selective proviral integration site in Moloney murine leukemia virus kinase 1 (PIM1) inhibitor from a screening-hit compound. J.Med.Chem., 55:5151-5164, 2012 Cited by PubMed Abstract: Serine/threonine kinase PIM1 is an emerging therapeutic target for hematopoietic and prostate cancer therapy. To develop a novel PIM1 inhibitor, we focused on 1, a metabolically labile, nonselective kinase inhibitor discovered in our previous screening study. We adopted a rational optimization strategy based mainly on structural information for the PIM1-1 complex to improve the potency and selectivity. This approach afforded the potent and metabolically stable PIM1-selective inhibitor 14, which shows only a marginal increase in molecular weight compared with 1 but has a significantly decreased cLogP. The validity of our design concept was confirmed by X-ray structure analysis. In a cellular study, 14 potently inhibited the growth of human leukemia cell line MV4-11 but had a negligible effect on the growth of WI-38 (surrogate for general toxicity). These results demonstrate the effectiveness of our design strategy for evolving the screening-hit compound 1 into a novel type of PIM1 inhibitor, 14. PubMed: 22540945DOI: 10.1021/jm3001289 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.08 Å) |
Structure validation
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