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

IF 0.9 4区 生物学
Lorien J Parker, Hisami Watanabe, Keiko Tsuganezawa, Yuri Tomabechi, Noriko Handa, Mikako Shirouzu, Hitomi Yuki, Teruki Honma, Naoko Ogawa, Tetsuo Nagano, Shigeyuki Yokoyama, Akiko Tanaka
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引用次数: 0

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.

Pim-1 激酶 P 环的灵活性:观察与抑制剂相互作用诱导的新构象。
丝氨酸/苏氨酸激酶 Pim-1 正在成为一种有前途的癌症治疗靶点。最近,人们将大量注意力集中在确定潜在的 Pim-1 候选抑制剂上,以治疗造血恶性肿瘤。最近报道了一个合理药物设计项目的成果[Nakano 等人 (2012),J. Med. Chem. 55, 5151-5156]。该报告描述了结构-活性关系的优化过程,并从药物化学的角度详细介绍了如何将最初从硅学筛选中发现的低效、非选择性化合物开发成强效、选择性和代谢稳定的 Pim-1 抑制剂。在此,报告了硅学中最初发现的化合物的结构,并描述了 Pim-1 复合物结构的显著特点。其中一个初始化合物--(Z)-7-(氮杂庚烷-1-基甲基)-2-[(1H-吲哚-3-基)亚甲基]-6-羟基-1-苯并呋喃-3(2H)-酮(化合物 1)中观察到了富含甘氨酸的 P 环区域的重排,所有其他衍生物中也发现了这种重排。这种新颖的 P 环构象似乎是通过与位于结合位点上方的 β3 链的额外相互作用而稳定下来的,这在 Pim-1 结构中并不常见。
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审稿时长
2-4 weeks
期刊介绍: Acta Crystallographica Section F is a rapid structural biology communications journal. Articles on any aspect of structural biology, including structures determined using high-throughput methods or from iterative studies such as those used in the pharmaceutical industry, are welcomed by the journal. The journal offers the option of open access, and all communications benefit from unlimited free use of colour illustrations and no page charges. Authors are encouraged to submit multimedia content for publication with their articles. Acta Cryst. F has a dedicated online tool called publBio that is designed to make the preparation and submission of articles easier for authors.
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