title: Synthesis and Biological Evaluation of Pyrazolo[1,5-a]pyrimidine Compounds as Potent and Selective Pim-1 Inhibitors.
abstract: Pim-1 has emerged as an attractive target for developing therapeutic agents for treating disorders involving abnormal cell growth, especially cancers. Herein we present lead optimization, chemical synthesis and biological evaluation of pyrazolo[1,5-a]pyrimidine compounds as potent and selective inhibitors of Pim-1 starting from a hit from virtual screening. These pyrazolo[1,5-a]pyrimidine compounds strongly inhibited Pim-1 and Flt-3 kinases. Selected compounds suppressed both the phosphorylation of BAD protein in a cell-based assay and 2-dimensional colony formation in a clonogenic cell survival assay at submicromolar potency, suggesting that cellular activity was mediated through inhibition of Pim-1. Moreover, these Pim-1 inhibitors did not show significant hERG inhibition at 30 μM concentration. The lead compound proved to be highly selective against a panel of 119 oncogenic kinases, indicating it had an improved safety profile compared with the first generation Pim-1 inhibitor SGI-1776.
authors.affiliation: Astex Pharmaceuticals, Inc. , 4140 Dublin Boulevard, Suite 200, Dublin, California 94568 United States.
authors.forename: Yong
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Astex Pharmaceuticals, Inc. , 4140 Dublin Boulevard, Suite 200, Dublin, California 94568 United States.
authors.forename: Benjamin G
authors.initials: BG
authors.lastname: Brenning
authors.affiliation: Astex Pharmaceuticals, Inc. , 4140 Dublin Boulevard, Suite 200, Dublin, California 94568 United States.
authors.forename: Steven G
authors.initials: SG
authors.lastname: Kultgen
authors.affiliation: Astex Pharmaceuticals, Inc. , 4140 Dublin Boulevard, Suite 200, Dublin, California 94568 United States.
authors.forename: Jason M
authors.initials: JM
authors.lastname: Foulks
authors.affiliation: Astex Pharmaceuticals, Inc. , 4140 Dublin Boulevard, Suite 200, Dublin, California 94568 United States.
authors.forename: Adrianne
authors.initials: A
authors.lastname: Clifford
authors.affiliation: Astex Pharmaceuticals, Inc. , 4140 Dublin Boulevard, Suite 200, Dublin, California 94568 United States.
authors.forename: Shuping
authors.initials: S
authors.lastname: Lai
authors.affiliation: Astex Pharmaceuticals, Inc. , 4140 Dublin Boulevard, Suite 200, Dublin, California 94568 United States.
authors.forename: Ashley
authors.initials: A
authors.lastname: Chan
authors.affiliation: Astex Pharmaceuticals, Inc. , 4140 Dublin Boulevard, Suite 200, Dublin, California 94568 United States.
authors.forename: Shannon
authors.initials: S
authors.lastname: Merx
authors.affiliation: Astex Pharmaceuticals, Inc. , 4140 Dublin Boulevard, Suite 200, Dublin, California 94568 United States.
authors.forename: Michael V
authors.initials: MV
authors.lastname: McCullar
authors.affiliation: Astex Pharmaceuticals, Inc. , 4140 Dublin Boulevard, Suite 200, Dublin, California 94568 United States.
authors.forename: Steven B
authors.initials: SB
authors.lastname: Kanner
authors.affiliation: Astex Pharmaceuticals, Inc. , 4140 Dublin Boulevard, Suite 200, Dublin, California 94568 United States.
authors.forename: Koc-Kan
authors.initials: KK
authors.lastname: Ho
keywords: 2-dimensional colony formation; BAD phosphorylation; Pim-1 inhibitor; Pyrazolo[1,5-a]pyrimidine; hERG inhibition; kinase selectivity