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

Abstract

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 <i>Zmpste24</i>-deficient mice. However, we don't know whether <i>Icmt</i> 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 <i>Icmt</i> 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 <i>Zmpste24</i>-deficient mouse fibroblasts. Importantly, C75 did not influence proliferation of wild-type human cells or <i>Zmpste24</i>-deficient mouse cells lacking <i>Icmt</i>, indicating drug specificity. These results raise hopes that ICMT inhibitors could be useful for treating children with HGPS.