CoREST Complex-Selective Histone Deacetylase Inhibitors Show Prosynaptic Effects and an Improved Safety Profile To Enable Treatment of Synaptopathies

Abstract

Synaptic dysfunction is a pathological feature in many neurodegenerative disorders, including Alzheimer’s disease, and synaptic loss correlates closely with cognitive decline. Histone deacetylases (HDACs) are involved in chromatin remodeling and gene expression and have been shown to regulate synaptogenesis and synaptic plasticity, thus providing an attractive drug discovery target for promoting synaptic growth and function. To date, HDAC inhibitor compounds with prosynaptic effects are plagued by known HDAC dose-limiting hematological toxicities, precluding their application to treating chronic neurologic conditions. We have identified a series of novel HDAC inhibitor compounds that selectively inhibit the HDAC–co-repressor of repressor element-1 silencing transcription factor (CoREST) complex while minimizing hematological side effects. HDAC1 and HDAC2 associate with multiple co-repressor complexes including CoREST, which regulates neuronal gene expression. We show that selectively targeting the CoREST co-repressor complex with the representative compound Rodin-A results in increased spine density and synaptic proteins, and improved long-term potentiation in a mouse model at doses that provide a substantial safety margin that would enable chronic treatment. The CoREST-selective HDAC inhibitor Rodin-A thus represents a promising therapeutic strategy in targeting synaptic pathology involved in neurologic disorders.

Histone deacetylases as targets for the treatment of neurodegenerative disorders: Challenges and future opportunities

“…126 In addition, modifications at the ZBG of a hydroxamic acid, which is the most common ZBG employed for the development of HDACis, 127 to an orthoaminoanilide moiety can lead to selective inhibition of HDAC1, 2, and 3, 55,127 while additional modifications in this ZBG through the insertion of heteroaromatic rings can result in the exploitation of additional interactions with an internal cavity, known as the foot pocket ( Figure 3A), 83,84 present in the structure of HDAC1 and 2, and, consequently, trigger selective inhibition of these two isoforms over HDAC3. 55 It is important to highlight that the kinetics related to the binding of the hydroxamic acid and ortho-aminoanilide moiety to Zn 2+ are different, in which the ortho-aminoanilide have a highest residence time in the active site. 84 It has been shown that the selective inhibition of class IIa (HDAC4, 5, 7, and 9) can also be achieved through an exploration of a selectivity cavity on the surface of these isoforms adjacent to the zinc channel, which is specific for this HDAC subfamily.…”

“…54,144 The diamino-aniline core of CI-994 (3) and Cpd-60 (8) was replaced by a diamino-heterocycle group in Rodin-A (9), maintaining the Zn +2 -chelating capacity and occupying the "foot pocket" at the same time ( Figure 7). 55 Cpd-60 (8) is more potent in inhibiting class I HDACs (HDAC1, HDAC2, and HDAC3) than Rodin-A (9), but similar to CI-994 (3), it displays hematological toxicity, causing severe toxic effects on myeloid and erythroid progenitor cells. Rodin-A (9) has been shown to minimize hematological side effects, and it has a similar IC 50 profile on the CoREST complex, HDAC1 and HDAC2 when compared with CI-994 (3).…”

“…53,54 The inhibition of the activity of HDACs in the CoREST complex has been shown to be a promising therapeutic strategy in targeting synaptic pathology involved in NDs, such as AD. 55 The CoREST complex represses neuronal gene expression by combining histone deacetylation with demethylation, 54 and its selective inhibition by HDACis was associated with increased levels of AcH3K9 in K562 cells, increased synaptic density in vivo and improved long-term potentiation (LTP) in a 5xFAD transgenic mouse model of amyloid pathology. 55 The class IIa (HDAC4, HDAC5, HDAC7, and HDAC9) isoenzymes are characterized by having a deacetylase domain in the C-terminal region and an N-terminal adapter domain, which has conserved binding sites for myocyte enhancement factor 2 (MEF2).…”

More than a Corepressor: The Role of CoREST Proteins in Neurodevelopment

“…The dual-hybrid agent has been successfully used as a potential therapeutic in cancer studies by reducing the proliferation of mouse melanoma cells through blocking the active sites of HDAC1 and LSD1 of the LCH complex (Kalin et al, 2018). Synaptic dysfunction is a common in many neurodegenerative diseases including AD, with HDACs involved in regulating synaptogenesis and synaptic plasticity (Fuller et al, 2019). HDAC inhibitors have been trialed to improve synaptic growth and function, but have been limited due to their off-target effects and dose-limiting hematologic toxicities.…”

“…HDAC inhibitors have been trialed to improve synaptic growth and function, but have been limited due to their off-target effects and dose-limiting hematologic toxicities. Fuller et al (2019) used the CoREST-selective HDAC inhibitor Rodin-A in a mouse model and were successful in increasing spine density, expression of synaptic proteins and long-term potentiation at suitable doses to allow for chronic treatment. This study has shown that selectively targeting the CoREST complex, and not the Sin3, NCoR, and NuRD complexes, offers a promising therapeutic for synaptopathies and that the CoREST complex is a key regulator of synaptic growth and function (Fuller et al, 2019).…”