Modelling-filtered drug repurposing and first-in-protein SPR validation of histone deacetylase 4 inhibitors for Ataxia-telangiectasia

: Ataxia-telangiectasia is a neurodegenerative disorder characterised by ATM deficiency and aberrant nuclear accumulation of Histone deacetylase 4 (HDAC4) in Purkinje neurons. Targeting HDAC4 has thus emerged as a promising therapeutic strategy. Here, we employed a drug-repositioning approach to identify new HDAC4 modulators from an EMA-approved compound library. In silico screening selected asenapine, a second-generation antipsychotic, through consensus scoring across four independent docking functions and low predicted binding free energy (ΔG), positioning it among the most thermodynamically stable candidates. Surface plasmon resonance analysis confirmed high-affinity binding to immobilised HDAC4, enabling extraction of kinetic and thermodynamic parameters that characterise the allosteric mechanism underlying HDAC4-asenapine complex formation. Competitive assay with tasquinimod, a known HDAC4 modulator, revealed that asenapine exhibits higher affinity supporting its candidacy for further pharmacological development. These findings underscore the utility of combining repositioning pipelines with real-time affinity quantification to accelerate the discovery of selective HDAC4-targeted therapeutics for Ataxia-Telangiectasia.