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
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
收藏
页码:6097 / 6103
页数:7
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