Identifying Lysophosphatidic Acid Acyltransferase β (LPAAT-β) as the Target of a Nanomolar Angiogenesis Inhibitor from a Phenotypic Screen Using the Polypharmacology Browser PPB2

被引：14

作者：

Poirier, Marion ^{[1
]}

Awale, Mahendra ^{[1
]}

Roelli, Matthias A. ^{[2
]}

Giuffredi, Guy T. ^{[1
]}

Ruddigkeit, Lars ^{[1
]}

Evensen, Lasse ^{[3
]}

Stooss, Amandine ^{[2
]}

Calarco, Serafina ^{[2
]}

Lorens, James B. ^{[3
]}

Charles, Roch-Philippe ^{[2
]}

Reymond, Jean-Louis ^{[1
]}

机构：

[1] Univ Bern, Natl Ctr Competence Res NCCR TransCure, Dept Chem & Biochem, Freiestr 3, CH-3012 Bern, Switzerland

[2] Univ Bern, Natl Ctr Competence Res NCCR TransCure, Inst Biochem & Mol Med, Buhlstr 28, CH-3000 Bern 9, Switzerland

[3] Univ Bergen, Dept Biomed, Ctr Canc Biomarkers CCBIO, Jonas Lies Vei 91, N-5009 Bergen, Norway

来源：

CHEMMEDCHEM | 2019年 / 14卷 / 02期

基金：

瑞士国家科学基金会;

关键词：

angiogenesis; kinase inhibitors; phenotypic screening; polypharmacology; target prediction; SMALL-MOLECULE INHIBITOR; KINASE INHIBITOR; GROWTH; CELLS; AXL; IDENTIFICATION; PREDICTION; VISUALIZATION; APOPTOSIS; SURVIVAL;

D O I：

10.1002/cmdc.201800554

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

By screening a focused library of kinase inhibitor analogues in a phenotypic co-culture assay for angiogenesis inhibition, we identified an aminotriazine that acts as a cytostatic nanomolar inhibitor. However, this aminotriazine was found to be completely inactive in a whole-kinome profiling assay. To decipher its mechanism of action, we used the online target prediction tool PPB2 (), which suggested lysophosphatidic acid acyltransferase beta (LPAAT-beta) as a possible target for this aminotriazine as well as several analogues identified by structure-activity relationship profiling. LPAAT-beta inhibition (IC50 approximate to 15 nm) was confirmed in a biochemical assay and by its effects on cell proliferation in comparison with a known LPAAT-beta inhibitor. These experiments illustrate the value of target-prediction tools to guide target identification for phenotypic screening hits and significantly expand the rather limited pharmacology of LPAAT-beta inhibitors.

引用

页码：224 / 236

页数：13