sw-100

Description: SW-100, a tetrahydroquinoline-based compound, is a novel, potent, brain penetrant and selective histone deacetylase 6 (HDAC6) inhibitor with an IC50 of 2.3 nM, it shows at least 1000-fold selectivity for HDAC6 relative to all other HDAC isozymes. SW-100 displays a significantly improved ability to cross the blood-brain-barrier. Disease-modifying therapies are needed for Fragile X Syndrome (FXS), as at present there are no effective treatments or cures. SW-100 is able 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 (IC50 = 2.3 nM), with at least a thousand-fold selectivity over all other class I, II, and IV HDAC isoforms. Moreover, through its inhibition of the alpha-tubulin deacetylase domain of HDAC6 (CD2), in cells SW-100 upregulates alpha-tubulin acetylation with no effect on histone acetylation and selectively restores the impaired acetylated alpha-tubulin levels in the hippocampus of Fmr1-/- mice. Lastly, SW-100 ameliorates several memory and learning impairments in Fmr1-/- mice, thus modeling the intellectual deficiencies associated with FXS, and hence providing a strong rationale for pursuing HDAC6-based therapies for the treatment of this rare disease.

References: ACS Chem Neurosci. 2019 Mar 20; 10(3):1679-1695.