DESIGN, SYNTHESIS, AND BIOLOGICAL STUDY OF HISTONE DEACETYLASE2 INHIBITORS TO ENHANCE MEMORY FORMATION

Abstract

Histone deacetylase 2 (HDAC2) is a critical regulator of neurocognitive functions. Its suppression is linked to improved memory and mitigation of Alzheimer’s disease (AD) pathologies by enhancing neuronal plasticity. However, the structural similarity among class-I HDACs has posed challenges in developing selective HDAC2 inhibitors.In this study, we report on the synthesis and characterization of a novel small-molecule HDAC2 inhibitor, JRM-28, to achieve selectivity and neuronal plasticity. JRM-28, initially synthesized as a prodrug with disulfide-linked monomers, demonstrated selective inhibition of HDAC2 with an IC50 of 0.107 µM. Comparative binding assays with other HDACs and in-silico docking studies further validated its specificity for HDAC2 over other HDACs. Functional evaluations revealed that JRM-28 induces morphological plasticity in neurons, evidenced by dendritic morphogenesis, spine maturation, and enhanced post-synaptic neurotransmission in both SHSY5Y and primary hippocampal neurons. Mechanistically, JRM-28 inactivated HDAC2, triggering the transcriptional activation of CREB (cAMP response element-binding protein), a central regulator of neuronal plasticity. This effect was selective for CREB, with no activation of related transcription factors CREM or ATF-1. When applied to AD neurons derived from iPSC-derived neural stem cells, JRM-28 upregulated CREB-dependent proteins, such as NR2A and GluR1, and stimulated NMDA- and AMPA-driven calcium influx, thereby enhancing neuronal plasticity and synaptic function. CREB silencing confirmed its essential role in mediating these effects. Our findings highlight JRM-28 as a promising small molecule for selective HDAC2 inhibition, offering a potential therapeutic approach to restore neuronal plasticity and cognitive functions in neurodegenerative diseases like AD.