Impaired Regulation of Histone Methylation and Acetylation Underlies Specific Neurodevelopmental Disorders.

Epigenetic processes are critical for governing the complex spatiotemporal patterns of gene expression in neurodevelopment. One such mechanism is the dynamic network of post-translational histone modifications that facilitate recruitment of transcription factors or even directly alter chromatin structure to modulate gene expression. This is a tightly regulated system, and mutations affecting the function of a single histone-modifying enzyme can shift the normal epigenetic balance and cause detrimental developmental consequences.

Brain Penetrable Histone Deacetylase 6 Inhibitor SW-100 Ameliorates Memory and Learning Impairments in a Mouse Model of Fragile X Syndrome.

Disease-modifying therapies are needed for Fragile X Syndrome (FXS), as at present there are no effective treatments or cures. Herein, we report on a tetrahydroquinoline-based selective histone deacetylase 6 (HDAC6) inhibitor SW-100, its pharmacological and ADMET properties, and its ability to improve upon memory performance in a mouse model of FXS, Fmr1 mice. This small molecule demonstrates good brain penetrance, low-nanomolar potency for the inhibition of HDAC6 (IC = 2.