DNA-Encoded Library Screening Identifies Benzo[b][1,4]oxazepin-4-ones as Highly Potent and Monoselective Receptor Interacting Protein 1 Kinase Inhibitors

被引：233

作者：

Harris, Philip A. ^{[1
]}

King, Bryan W. ^{[2
]}

Bandyopadhyay, Deepak ^{[2
]}

Berger, Scott B. ^{[1
]}

Campobasso, Nino ^{[2
]}

Capriotti, Carol A. ^{[1
]}

Cox, Julie A. ^{[2
]}

Dare, Lauren ^{[1
]}

Dong, Xiaoyang ^{[1
]}

Finger, Joshua N. ^{[1
]}

Grady, LaShadric C. ^{[3
]}

Hoffmann, Sandra J. ^{[1
]}

Jeong, Jae U. ^{[1
]}

Kang, James ^{[1
]}

Kasparcova, Viera ^{[1
]}

Lakdawala, Ami S. ^{[2
]}

Lehr, Ruth ^{[2
]}

McNulty, Dean E. ^{[2
]}

Nagilla, Rakesh ^{[1
]}

Ouellette, Michael T. ^{[2
]}

Pao, Christina S. ^{[2
]}

Rendina, Alan R. ^{[2
]}

Schaeffer, Michelle C. ^{[2
]}

Summerfield, Jennifer D. ^{[3
]}

Swift, Barbara A. ^{[1
]}

Totoritis, Rachel D. ^{[2
]}

Ward, Paris ^{[2
]}

Zhang, Aming ^{[4
]}

Zhang, Daohua ^{[1
]}

Marquis, Robert W. ^{[1
]}

Bertin, John ^{[1
]}

Gough, Peter J. ^{[1
]}

机构：

[1] GlaxoSmithKline, Pattern Recognit Receptor Discovery Performance U, Collegeville Rd, Collegeville, PA 19426 USA

[2] GlaxoSmithKline, Platform Technol & Sci, Collegeville Rd, Collegeville, PA 19426 USA

[3] GlaxoSmithKline, Platform Technol & Sci, Winter St, Waltham, MA 02451 USA

[4] GlaxoSmithKline, Platform Technol & Sci, King Of Prussia, PA 19406 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2016年 / 59卷 / 05期

关键词：

SMALL-MOLECULE LIBRARIES; RIP1; KINASE; STRUCTURAL BASIS; CELL-DEATH; TNF-ALPHA; INFLAMMATION; NECROPTOSIS; NECROSTATINS; DISCOVERY; BINDING;

D O I：

10.1021/acs.jmedchem.5b01898

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The recent discovery of the role of receptor interacting protein 1 (RIP 1) kinase in tumor necrosis factor (TNF)-mediated inflammation has led to its emergence as a highly promising target for the treatment of multiple inflammatory diseases. We screened RIP1 against GSK's DNA-encoded small-molecule libraries and identified a novel highly potent benzoxazepinone inhibitor series. We demonstrate that this template possesses complete monakinase selectivity for RIP1 plus unique species selectivity for primate versus. nonprimate RIP1. We elucidate the conformation of RIP1 bound to this benzoxazepinone inhibitor driving its high kinase selectivity and design specific mutations in murine RIP1 to restore potency to levels similar to primate RIP1. This series differentiates itself from known RIP1 inhibitors in combining high potency and kinase selectivity with good pharmacokinetic profiles in rodents. The favorable developability profile of this benzoxazepinone template, as exemplified by compound 14 (GSK'481), makes it an excellent starting point for further optimization into a RIP1 clinical candidate.

引用

页码：2163 / 2178

页数：16

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