The design, synthesis, and biological evaluation of PIM kinase inhibitors

被引：31

作者：

Tsuhako, Amy Lew ^{[1
]}

Brown, David S. ^{[1
]}

Koltun, Elena S. ^{[1
]}

Aay, Naing ^{[1
]}

Arcalas, Arlyn ^{[1
]}

Chan, Vicky ^{[1
]}

Du, Hongwang ^{[1
]}

Engst, Stefan ^{[1
]}

Franzini, Maurizio ^{[1
]}

Galan, Adam ^{[1
]}

Huang, Ping ^{[1
]}

Johnston, Stuart ^{[1
]}

Kane, Brian ^{[1
]}

Kim, Moon H. ^{[1
]}

Laird, A. Douglas ^{[1
]}

Lin, Rui ^{[1
]}

Mock, Lillian ^{[1
]}

Ngan, Iris ^{[1
]}

Pack, Michael ^{[1
]}

Stott, Gordon ^{[1
]}

Stout, Thomas J. ^{[1
]}

Yu, Peiwen ^{[1
]}

Zaharia, Cristiana ^{[1
]}

Zhang, Wentao ^{[1
]}

Zhou, Peiwen ^{[1
]}

Nuss, John M. ^{[1
]}

Kearney, Patrick C. ^{[1
]}

Xu, Wei ^{[1
]}

机构：

[1] Exelixis, Dept Drug Discovery, San Francisco, CA 94080 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2012年 / 22卷 / 11期

关键词：

PIM-1; PIM-2; PIM-3; CK2; inhibitor; Cdc7; Benzofuropyrimidinone; STRUCTURAL BASIS; PROTEIN-KINASES; POTENT; IDENTIFICATION; DERIVATIVES; DISCOVERY; BINDING; UNIQUE;

D O I：

10.1016/j.bmcl.2012.04.025

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

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. (C) 2012 Elsevier Ltd. All rights reserved.

引用

页码：3732 / 3738

页数：7

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