The design, synthesis, and biological evaluation of PIM kinase inhibitors
- 作者：Amy Lew Tsuhako ; alew@exelixis.com ; amy.lew@gmail.com ; David S. Brown ; Elena S. Koltun ; Naing Aay ; Arlyn Arcalas ; Vicky Chan ; Hongwang Du ; Stefan Engst ; Maurizio Franzini ; Adam Galan ; Ping Huang ; Stuart Johnston ; Brian Kane ; Moon H. Kim ; A. Douglas Laird ; Rui Lin ; Lillian Mock ; Iris Ngan ; Michael Pack ; Gordon Stott ; Thomas J. Stout ; Peiwen Yu ; Cristiana Zaharia ; Wentao Zhang ; Peiwen Zhou ; John M. Nuss ; Patrick C. Kearney ; Wei Xu
- 关键词：PIM-1 ; PIM-2 ; PIM-3 ; CK2 inhibitor ; Cdc7 inhibitor ; Benzofuropyrimidinone
- 刊名：Bioorganic and Medicinal Chemistry Letters
- 出版年：2012
- 期刊代码：10_0960894x
- 类别：ch
- 出版时间：1 June, 2012
- 卷：22
- 期：11
- 页码：3732-3738
- 文件大小：1407 K
摘要
A series of substituted benzofuropyrimidinones with pan-PIM activities and excellent selectivity against a panel of diverse kinases is described. Initial exploration identified aryl benzofuropyrimidinones that were potent, but had cell permeability limitation. Using X-ray crystal structures of the bound PIM-1 complexes with 3, 5m, and 6d, we were able to guide the SAR and identify the alkyl benzofuropyrimidinone (6l) with good PIM potencies, permeability, and oral exposure.