title: Flexibility of the P-loop of Pim-1 kinase: observation of a novel conformation induced by interaction with an inhibitor.
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.
authors.affiliation: RIKEN Systems and Structural Biology Center, 1-7-22 Suehiro-cho, Tsurumi, Yokohama 230-0045, Japan.
authors.forename: Lorien J
authors.initials: LJ
authors.lastname: Parker
authors.forename: Hisami
authors.initials: H
authors.lastname: Watanabe
authors.forename: Keiko
authors.initials: K
authors.lastname: Tsuganezawa
authors.forename: Yuri
authors.initials: Y
authors.lastname: Tomabechi
authors.forename: Noriko
authors.initials: N
authors.lastname: Handa
authors.forename: Mikako
authors.initials: M
authors.lastname: Shirouzu
authors.forename: Hitomi
authors.initials: H
authors.lastname: Yuki
authors.forename: Teruki
authors.initials: T
authors.lastname: Honma
authors.forename: Naoko
authors.initials: N
authors.lastname: Ogawa
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Nagano
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Yokoyama
authors.forename: Akiko
authors.initials: A
authors.lastname: Tanaka
mesh_terms: D018360:Crystallography, X-Ray; D006801:Humans; D006860:Hydrogen Bonding; D008958:Models, Molecular; D054730:Protein Interaction Domains and Motifs; D047428:Protein Kinase Inhibitors / Q000737:chemistry*; D020836:Protein Structure, Quaternary; D051573:Proto-Oncogene Proteins c-pim-1 / Q000737:chemistry*; D040681:Structural Homology, Protein
chemical_list: D047428:Protein Kinase Inhibitors; D051573:Proto-Oncogene Proteins c-pim-1