跳转至内容
Merck
  • A small-molecule ICMT inhibitor delays senescence of Hutchinson-Gilford progeria syndrome cells.

A small-molecule ICMT inhibitor delays senescence of Hutchinson-Gilford progeria syndrome cells.

eLife (2021-02-03)
Xue Chen, Haidong Yao, Muhammad Kashif, Gwladys Revêchon, Maria Eriksson, Jianjiang Hu, Ting Wang, Yiran Liu, Elin Tüksammel, Staffan Strömblad, Ian M Ahearn, Mark R Philips, Clotilde Wiel, Mohamed X Ibrahim, Martin O Bergo
摘要

A farnesylated and methylated form of prelamin A called progerin causes Hutchinson-Gilford progeria syndrome (HGPS). Inhibiting progerin methylation by inactivating the isoprenylcysteine carboxylmethyltransferase (ICMT) gene stimulates proliferation of HGPS cells and improves survival of Zmpste24-deficient mice. However, we don't know whether Icmt inactivation improves phenotypes in an authentic HGPS mouse model. Moreover, it is unknown whether pharmacologic targeting of ICMT would be tolerated by cells and produce similar cellular effects as genetic inactivation. Here, we show that knockout of Icmt improves survival of HGPS mice and restores vascular smooth muscle cell numbers in the aorta. We also synthesized a potent ICMT inhibitor called C75 and found that it delays senescence and stimulates proliferation of late-passage HGPS cells and Zmpste24-deficient mouse fibroblasts. Importantly, C75 did not influence proliferation of wild-type human cells or Zmpste24-deficient mouse cells lacking Icmt, indicating drug specificity. These results raise hopes that ICMT inhibitors could be useful for treating children with HGPS.

材料
货号
品牌
产品描述

Sigma-Aldrich
环己酰亚胺 溶液, Ready-Made Solution, microbial, 100 mg/mL in DMSO, Suitable for cell culture
Sigma-Aldrich
抗磷酸组蛋白H2A.X(Ser139)抗体,克隆JBW301, clone JBW301, Upstate®, from mouse
Sigma-Aldrich
抗-β-微管蛋白III 兔抗, affinity isolated antibody, buffered aqueous solution
Sigma-Aldrich
早老蛋白抗体,克隆13A4, clone 13A4, Upstate®, from mouse
Sigma-Aldrich
洛那法尼布, ≥98% (HPLC)
Sigma-Aldrich
抗鼠 IgG(全分子)− 过氧化物酶 兔抗, IgG fraction of antiserum, buffered aqueous solution
Sigma-Aldrich
抗-Prelamin-A抗体,克隆7G11, clone 7G11, from rat