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

• DOI: 10.1038/s42003-020-01540-w
• Publication Date: 2021-01-04T11:02:41Z
• Authors: So-mi Kang; Min-Ho Yoon; Jinsook Ahn; Ji-Eun Kim; So Young Kim; Seock Yong Kang; Jeongmin Joo; Soyoung Park; Jung-Hyun Cho; Tae-Gyun Woo; Ah-Young Oh; Kyu Jin Chung; So Yon An; Tae Sung Hwang; Soo Yong Lee; Jeong-Su Kim; Nam-Chul Ha; Gyu-Yong Song; Bum-Joon Park
• Keywords: Male; 0301 basic medicine; Adolescent; QH301-705.5; Primary Cell Culture; Drug Evaluation, Preclinical; Lamin Type A; Article; 3. Good health; Disease Models, Animal; Mice; 03 medical and health sciences; HEK293 Cells; Progeria; Animals; Humans; Female; Biology (General); Child

AbstractPrevious 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 LmnaG609G/G609G mouse for about 10 weeks and increase its body weight. Progerinin can also extend the life span of LmnaG609G/+ mouse for about 14 weeks via oral administration, whereas treatment with lonafarnib (farnesyl-transferase inhibitor) can only extend the life span of LmnaG609G/+ mouse for about two weeks. In addition, progerinin can induce histological and physiological improvement in LmnaG609G/+ mouse. These results indicate that progerinin is a strong drug candidate for HGPS.