Progerinin, an optimized progerin-lamin A binding inhibitor, ameliorates premature senescence phenotypes of Hutchinson-Gilford progeria syndrome

Abstract

Previous work has revealed that progerin-lamin A binding inhibitor (JH4) can ameliorate pathological features of Hutchinson-Gilford progeria syndrome (HGPS) such as nuclear deformation, growth suppression in patient's cells, and very short life span in an in vivo mouse model. Despite its favorable effects, JH4 is rapidly eliminated in in vivo pharmacokinetic (PK) analysis. Thus, we improved its property through chemical modification and obtained an optimized drug candidate, Progerinin (SLC-D011). This chemical can extend the life span of Lmna(G609G/G609G) mouse for about 10 weeks and increase its body weight. Progerinin can also extend the life span of Lmna(G609G/+) mouse for about 14 weeks via oral administration, whereas treatment with lonafarnib (farnesyl-transferase inhibitor) can only extend the life span of Lmna(G609G/+) mouse for about two weeks. In addition, progerinin can induce histological and physiological improvement in Lmna(G609G/+) mouse. These results indicate that progerinin is a strong drug candidate for HGPS. Kang, Park and colleagues develop and demonstrate the effects of a new drug candidate for treatment of Hutchinson-Gilford progeria syndrome pathologies. Progerinin extends the life span of mice used to model this disease and induces histological and physiological improvements.