Hit to Lead Account of the Discovery of a New Class of Inhibitors of Pim Kinases and Crystallographic Studies Revealing an Unusual Kinase Binding Mode†
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- 作者：Kevin Qian‡ ; ; Lian Wang‡ ; ; Charles L. Cywin ; Bennett T. Farmer ; ; Eugene Hickey ; Carol Homon ; Scott Jakes ; Mohammed A. Kashem ; George Lee ; Scott Leonard ; Jun Li ; Ronald
- 刊名：Journal of Medicinal Chemistry
- 出版年：2009
- 出版时间：April 9, 2009
- 年：2009
- 卷：52
- 期：7
- 页码：1814-1827
- 全文大小：304K
- 年卷期：v.52,no.7(April 9, 2009)
- ISSN：1520-4804
文摘
A series of inhibitors of Pim-2 kinase identified by high-throughput screening is described. Details of the hit validation and lead generation process and structure−activity relationship (SAR) studies are presented. Disclosure of an unconventional binding mode for 1, as revealed by X-ray crystallography using the highly homologous Pim-1 protein, is also presented, and observed binding features are shown to correlate with the Pim-2 SAR. While highly selective within the kinase family, the series shows similar potency for both Pim-1 and Pim-2, which was expected on the basis of homology, but unusual in light of reports in the literature documenting a bias for Pim-1. A rationale for these observations based on Pim-1 and Pim-2 KM(ATP) values is suggested. Some interesting cross reactivity with casein kinase-2 was also identified, and structural features which may contribute to the association are discussed.