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Acta Crystallogr Sect F Struct Biol Cryst Commun. 2012 Aug 1;68(Pt 8):860-6. doi: 10.1107/S1744309112027108. Epub 2012 Jul 31.

Flexibility of the P-loop of Pim-1 kinase: observation of a novel conformation induced by interaction with an inhibitor.

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  • 1RIKEN Systems and Structural Biology Center, 1-7-22 Suehiro-cho, Tsurumi, Yokohama 230-0045, Japan.

Abstract

The serine/threonine kinase Pim-1 is emerging as a promising target for cancer therapeutics. Much attention has recently been focused on identifying potential Pim-1 inhibitor candidates for the treatment of haematopoietic malignancies. The outcome of a rational drug-design project has recently been reported [Nakano et al. (2012), J. Med. Chem. 55, 5151-5156]. The report described the process of optimization of the structure-activity relationship and detailed from a medicinal chemistry perspective the development of a low-potency and nonselective compound initially identified from in silico screening into a potent, selective and metabolically stable Pim-1 inhibitor. Here, the structures of the initial in silico hits are reported and the noteworthy features of the Pim-1 complex structures are described. A particular focus was placed on the rearrangement of the glycine-rich P-loop region that was observed for one of the initial compounds, (Z)-7-(azepan-1-ylmethyl)-2-[(1H-indol-3-yl)methylidene]-6-hydroxy-1-benzofuran-3(2H)-one (compound 1), and was also found in all further derivatives. This novel P-loop conformation, which appears to be stabilized by an additional interaction with the β3 strand located above the binding site, is not usually observed in Pim-1 structures.

PMID:
22869110
[PubMed - indexed for MEDLINE]
PMCID:
PMC3412761
Free PMC Article

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