Indolyl-Pyridinyl-Propenone-Induced Methuosis through the Inhibition of PIKFYVE

被引：29

作者：

Cho, Hyelim ^{[1
,3
]}

Geno, Erin ^{[1
,4
]}

Patoor, Maude ^{[1
]}

Reid, Adam ^{[2
]}

McDonald, Rick ^{[1
]}

Hild, Marc ^{[1
]}

Jenkins, Jeremy L. ^{[1
]}

机构：

[1] Novartis Inst BioMed Res, Chem Biol & Therapeut, 181 Massachusetts Ave, Cambridge, MA 02139 USA

[2] Johns Hopkins Univ, Dept Chem, 3400 N Charles St, Baltimore, MD 21218 USA

[3] Merck Res Labs, Dept Pharmacol, 33 Ave Louis Pasteur, Boston, MA 02115 USA

[4] Vertex Pharmaceut, Dept Comp Sci, 50 Northern Ave, Boston, MA 02210 USA

来源：

ACS OMEGA | 2018年 / 3卷 / 06期

关键词：

NONAPOPTOTIC-CELL-DEATH; BIOLOGICAL EVALUATION; VACUOLIZATION; INDUCTION;

D O I：

10.1021/acsomega.8b00202

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

Methuosis is a form of nonapoptotic cell death characterized by the accumulation of macropinosome-derived vacuoles. Herein, we identify PIKFYVE, a class III phosphoinositide (PI) kinase, as the protein target responsible for the methuosisinducing activity of indolyl-pyridinyl-propenones (3-(5-methoxy-2-methyl-1H-indol-3-yl)1-(4-pyridinyl)-2-propen-1-one). We further characterize the effects of chemical substitutions at the 2-and 5-indolyl positions on cytoplasmic vacuolization and PIKFYVE binding and inhibitory activity. Our study provides a better understanding of the mechanism of methuosis-inducing indolyl-pyridinyl-propenones.

引用

页码：6097 / 6103

页数：7

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