A novel acetylated derivative of Tankyrase inhibitor ameliorates social deficits in a mouse model of autism spectrum disorder
LIU Hanze
WANG Yarong
WANG Shuo
YU Tiantian
WANG Jing
WANG Yazhou
WU Shengxi
WANG Mengmeng
GAO Feng
Abstract：Objective To investigate the effects of a novel esterified Tankyrase inhibitor(TNKI)on the social deficits in mice with autism spectrum disorder(ASD).Methods Esterification modification strategy was adopted to design and synthesize an acetylated TNKI(named as TNKI-Ac).Its inhibitory effects on Wnt signaling and glycolysis were evaluated using 293T cells and primary cortical neurons isolated from ASD mice(Shank3b-/-mice)through Western blotting,TOPflash assay,extracellular acidification rate,and intracellular lactate levels.The TNKI-Ac was administered to Shank3b-/-mice via tail vein injection,and its effects on social deficits were assessed by the three-chamber test,resident-intruder test and ultrasonic vocalization.Results Similar to the original TNKI,TNKI-Ac exhibited a dual inhibitory effect on Wnt signaling and glycolysis in both 293T cells and primary Shank3b-/-cortical neurons(P＜0.05).Superior to TNKI,tail vein injection of TNKI-Ac significantly ameliorated the social deficits(including social preference,social interaction and social communication)in Shank3b-/-mice(P＜0.05).Conclusion Esterification modification may improve the pharmacodynamic properties of TNKI to some extent.The acetylated derivative of TNKI can ameliorate the social deficits in ASD mice and may serve as a potential prodrug for further development.
Keywords：autism spectrum disordersocial deficitsWnt signalingglycolysisTankyrase inhibitorsmall-molecule compoundesterificationShank3b mutation
Publication Date：2026-06-30
Online Publishing Date：2026-08-26(First online date of this platform, not the publication date of the document)
Pages：7( 867-873 )