Histone Deacetylase Inhibitor Research Articles

Synthesis and evaluation of hybrid molecules as RIPK1 and HDACs dual inhibitors

Receptor-interacting protein kinase 1 (RIPK1) is a key target in the necroptosis signaling pathway, and histone deacetylases (HDACs) are crucial epigenetic modifiers for various proteins. Both RIPK1 and HDACs are critical for homeostasis and inflammation, and their dysfunction were observed concurrently in many diseases, including cancer, neurodegenerative disorders, acute injuries, inflammatory diseases, and autoimmune diseases. Thus, simultaneous inhibition of RIPK1 and HDACs may offer promising strategies for the treatment of these diseases. In this research, we adopted a hybrid design strategy and synthesized a series of RIPK1/HDACs dual inhibitors. Among them, compound 4 demonstrated potent inhibitory activities against both RIPK1 and HDACs with nanomolar level potency. Molecular docking and molecular dynamics (MD) simulations confirmed that compound 4 could bind to RIPK1 and HDAC6 with high affinity. Absorption, distribution, metabolism, excretion, and toxicity (ADMET) analysis suggested that compound 4 possesses promising drug-likeness profiles. Overall, this study provided potent RIPK1/HDACs dual inhibitor for future study of RIPK1 and HDACs in disease.

The Role of Short Chain Fatty Acids in Inflammation and Body Health.

Short chain fatty acids (SCFAs), mainly including acetate, propionate and butyrate, are produced by intestinal bacteria during the fermentation of partially digested and indigestible polysaccharides. SCFAs play an important role in regulating intestinal energy metabolism and maintaining the homeostasis of the intestinal environment and also play an important regulatory role in organs and tissues outside the gut. In recent years, many studies have shown that SCFAs can regulate inflammation and affect host health, and two main signaling mechanisms have also been identified: the activation of G-protein coupled receptors (GPCRs) and inhibition of histone deacetylase (HDAC). In addition, a growing body of evidence highlights the importance of every SCFA in influencing health maintenance and disease development. In this review, we summarized the recent advances concerning the biological properties of SCFAs and their signaling pathways in inflammation and body health. Hopefully, it can provide a systematic theoretical basis for the nutritional prevention and treatment of human diseases.

Comprehensive analysis of microRNAs modulated by histone deacetylase inhibitors identifies microRNA-7-5p with anti-myeloma effect.

Basic research to expand treatment options for multiple myeloma is greatly needed due to the refractory nature of the disease. Histone deacetylase (HDAC) inhibitors, which are epigenetic regulators, are attractive but have limited applications. MicroRNAs (miRNAs), which are also epigenetic regulators, are important molecules that may lead to future therapeutic breakthroughs. In this study, we comprehensively searched for miRNAs that are altered by HDAC inhibitors in myeloma cells. We identified miR-7-5p (miR-7) as a miRNA downregulated by HDAC inhibitors. Transfection of myeloma cell lines with miR-7 suppressed cell proliferation, induced apoptosis, and enhanced the effects of the HDAC inhibitor panobinostat. Expression of miR-7 was downregulated by c-Myc inhibition, but upregulated by bortezomib. Comprehensive examination of miR-7 targets revealed four candidates: SLC6A9, LRRC59, EXOSC2, and PSME3. Among these, we focused on PSME3, an oncogene involved in proteasome capacity in myeloma cells. PSME3 knockdown increases myeloma cell death and panobinostat sensitivity. In conclusion, miR-7, which is downregulated by HDAC inhibitors, is a tumor suppressor that targets PSME3. This miR-7 downregulation may be involved in HDAC inhibitor resistance. In addition, combinations of anti-myeloma drugs that complement changes in miRNA expression should be considered.

Neurodegenerative diseases associated with the disruption of proteostasis and their therapeutic strategies using chemical chaperones.

Aberrant proteostasis is thought to be involved in the pathogenesis of neurodegenerative diseases. Some proteostasis abnormalities are ameliorated by chaperones. Chaperones are divided into three groups: molecular, pharmacological and chemical. Chemical chaperones intended to alleviate stress in organelles, such as the endoplasmic reticulum (ER), are now being administered clinically. Of the chemical chaperones, 4-phenylbutyrate (4-PBA) has been used as a research reagent, and its mechanism of action includes chaperone effects and the inhibition of histone deacetylase. Moreover, it also binds to the B-site of SEC24 and regulates COPII-mediated transport from the ER. Although its therapeutic effect may not be strong, elucidating the mechanism of action of 4-PBA may contribute to the identification of novel therapeutic targets for neurodegenerative diseases.

Design and radiosynthesis of class-IIa HDAC inhibitor with high molar activity via repositioning the 18F-radiolabel

The design and radiosynthesis of [18F]NT376, a high potency inhibitor of class-IIa histone deacetylases (HDAC) is reported. We utilized a three-step radiochemical approach that led to the radiosynthesis of [18F]NT376 in a good radiochemical yield, (17.0 ± 3%, decay corrected), high radiochemical purity (> 97%) and relatively high molar activity of 185.0 GBq/µmol (> 5.0 Ci/µmol). The repositioning of the 18F-radiolabel into a phenyl ring (18F-Fluoro-aryl) of the class-IIa HDAC inhibitor avoided the shortcomings of the direct radiolabeling of the 5-trifluoromethyl-1,2,4-oxadiazole moiety that was reported by us previously and was associated with low molar activity (0.74–1.51 GBq/µmol, 20–41 mCi/µmol). This radiochemical approach could find a wider application for radiolabeling similar molecules with good radiochemical yield and high molar activity.

Development of Epigenetic Modifiers with Therapeutic Potential in FMS-Related Tyrosine Kinase 3/Internal Tandem Duplication (FLT3/ITD) Acute Myeloid Leukemia and Other Blood Malignancies.

Blood cancers encompass a group of diseases affecting the blood, bone marrow, or lymphatic system, representing the fourth most commonly diagnosed cancer worldwide. Leukemias are characterized by the dysregulated proliferation of myeloid and lymphoid cells with different rates of progression (acute or chronic). Among the chronic forms, hairy cell leukemia (HCL) is a rare disease, and no drugs have been approved to date. However, acute myeloid leukemia (AML) is one of the most aggressive malignancies, with a low survival rate, especially in cases with FLT3-ITD mutations. Epigenetic modifications have emerged as promising strategies for the treatment of blood cancers. Epigenetic modulators, such as histone deacetylase (HDAC) inhibitors, are increasingly used for targeted cancer therapy. New hydroxamic acid derivatives, preferentially inhibiting HDAC6 (5a-q), were developed and their efficacy was investigated in different blood cancers, including multiple myeloma (MM), HCL, and AML, pointing out their pro-apoptotic effect as the mechanism of cell death. Among the inhibitors described, 5c, 5g, and 5h were able to rescue the hematopoietic phenotype in vivo using the FLT3-ITD zebrafish model of AML. 5c (leuxinostat) proved its efficacy in cells from FLT3-ITD AML patients, promoting marked acetylation of α-tubulin compared to histone H3, thereby confirming HDAC6 as a preferential target for this new class of hydroxamic acid derivatives at the tested doses.

Epigenetic-based differentiation therapy for Acute Myeloid Leukemia

Despite the development of novel therapies for acute myeloid leukemia, outcomes remain poor for most patients, and therapeutic improvements are an urgent unmet need. Although treatment regimens promoting differentiation have succeeded in the treatment of acute promyelocytic leukemia, their role in other acute myeloid leukemia subtypes needs to be explored. Here we identify and characterize two lysine deacetylase inhibitors, CM-444 and CM-1758, exhibiting the capacity to promote myeloid differentiation in all acute myeloid leukemia subtypes at low non-cytotoxic doses, unlike other commercial histone deacetylase inhibitors. Analyzing the acetylome after CM-444 and CM-1758 treatment reveals modulation of non-histone proteins involved in the enhancer–promoter chromatin regulatory complex, including bromodomain proteins. This acetylation is essential for enhancing the expression of key transcription factors directly involved in the differentiation therapy induced by CM-444/CM-1758 in acute myeloid leukemia. In summary, these compounds may represent effective differentiation-based therapeutic agents across acute myeloid leukemia subtypes with a potential mechanism for the treatment of acute myeloid leukemia.

Chromatin context-dependent effects of epigenetic drugs on CRISPR-Cas9 editing.

The efficiency and outcome of CRISPR/Cas9 editing depends on the chromatin state at the cut site. It has been shown that changing the chromatin state can influence both the efficiency and repair outcome, and epigenetic drugs have been used to improve Cas9 editing. However, because the target proteins of these drugs are not homogeneously distributed across the genome, the efficacy of these drugs may be expected to vary from locus to locus. Here, we systematically analyzed this chromatin context-dependency for 160 epigenetic drugs. We used a human cell line with 19 stably integrated reporters to induce a double-stranded break in different chromatin environments. We then measured Cas9 editing efficiency and repair pathway usage by sequencing the mutational signatures. We identified 58 drugs that modulate Cas9 editing efficiency and/or repair outcome dependent on the local chromatin environment. For example, we find a subset of histone deacetylase inhibitors that improve Cas9 editing efficiency throughout all types of heterochromatin (e.g. PCI-24781), while others were only effective in euchromatin and H3K27me3-marked regions (e.g. apicidin). In summary, this study reveals that most epigenetic drugs alter CRISPR editing in a chromatin-dependent manner, and provides a resource to improve Cas9 editing more selectively at the desired location.

Combination Therapy with Immune Checkpoint Inhibitors and Histone Deacetylase Inhibitors or Alkylating Agents.

Immune checkpoint inhibitors (CPIs) have been widely adopted in a number of early and advanced malignancies. Histone deacetylase inhibitors (HDACis) and alkylating agents (AAs) have been suggested to potentiate the actions of CPIs on tumor cells. We conducted a comprehensive literature review to explore the potential synergistic activity between CPIs, AAs, and HDACis. Clinical and non-clinical studies describing outcomes in patients with cancer receiving CPIs and either concomitant or sequential (pre- or post-CPI) AAs or HDACis were identified in PubMed using pre-defined search strings. Manual searches of key oncology congresses were similarly performed. All relevant articles and abstracts were manually screened for relevance, classified according to the specific anticancer agents used (CPIs, AAs, or HDACis), tumor entity, and whether treatment was concomitant or sequential. Overall, 227 unique clinical studies across a range of tumor types, both solid tumors and hematological malignancies, were identified. One hundred and fifty-nine publications on Phase I and II clinical studies together with 41 publications on Phase III studies were examined. The most commonly investigated tumor types were melanoma, triple-negative breast cancer, non-small cell lung cancer, and Hodgkin lymphoma. The randomized clinical studies identified, all of which reported on the combination of a CPI with an AA, demonstrated superior outcomes in the combination arm compared with CPI or AA monotherapy. Similarly, combination therapy with CPIs and HDACis demonstrated promising activity. Sequential or concomitant administration of a CPI with an AA or an HDACi may improve outcomes for patients with a range of tumor types. There is a rationale to support further investigation into the potential for synergy between CPIs, alkylating agents and/or HDACis in both the non-clinical and clinical settings.

Discovering novel derivatives of STAT3 and HDAC inhibitors with anti-tumor activity.

In modern cancer therapy, blockage of more than one target is a standard approach, and there are already many dual-target drugs that can achieve multiple inhibition through a single molecule. Herein, we designed and synthesized a series of novel derivatives with signal transducer and activator of transcription 3 (STAT3) and histone deacetylase (HDAC) inhibitory activity through strategy of combining pharmacophore based on the STAT3 inhibitor E28 and HDAC inhibitor MS-275. Among them, compound 24 (IC50 = 8.22 ± 0.27 μM) showed better anti-tumor activity than the clinical Class I HDAC inhibitor MS-275 (IC50 = 14.65 ± 0.24 μM) in MCF-7 breast cancer cells. Furthermore, the dual inhibition to HDAC and STAT3 of compound 24 was validated by western blot analysis. The study provides new tool compounds for further exploration of STAT3-HDAC pathway inhibitor achieved with a single molecule.

Interrelated involvement of the endocannabinoid/endovanilloid (TRPV1) systems and epigenetic processes in anxiety- and working memory impairment-related behavioural effects of nicotine as a stressor.

The addictive use of nicotine contained in tobacco is associated with stressor-like emotional and cognitive effects such as anxiety and working memory impairment, and the involvement of epigenetic mechanisms such as histone acetylation has recently been reported. Although the precise nature of behavioural plasticity remains unclear, both anxiogenic- and working memory impairment-like effects were observed in the present experimental model of mice treated with repeated subcutaneous nicotine and/or immobilization stress, and these effects were commonly attenuated by the histone deacetylase (HDAC) inhibitors that induce histone acetylation. Such HDAC inhibitor-induced resilience was mimicked by ligands for the endocannabinoid (ECB) system, a neurotransmitter system that is closely associated with nicotine-induced addiction-related behaviours: the anxiogenic-like effects were mitigated by the cannabinoid type 1 (CB1) agonist arachidonylcyclopropylamide (ACPA), whereas the working memory impairment-like effects were mitigated by the CB1 antagonist SR 141716A. Moreover, the effects of the HDAC inhibitors were also mimicked by ligands for the endovanilloid (transient receptor potential vanilloid 1 [TRPV1]) system, a system that shares common characteristics with the ECB system: the anxiogenic-like effects were mitigated by the TRPV1 antagonist capsazepine, whereas the working memory impairment-like effects were mitigated by the TRPV1 agonist olvanil. Notably, the HDAC inhibitor-induced anxiolytic-like effects were attenuated by SR 141716A, which were further counteracted by capsazepine, whereas the working memory improvement-like effects were attenuated by capsazepine, which were further counteracted by SR 141716A. These results suggest the contribution of interrelated control of the ECB/TRPV1 systems and epigenetic processes such as histone acetylation to novel therapeutic approaches.

A Review on Indole as a Cardinal Scaffold for Anticancer Drugs Development

Abstract: Chemotherapy is the mainstay of therapeutic cancer therapy; however, the development of resistance typically makes it less effective. There are continuous efforts by researchers to find novel lead compounds with potent anti-cancer activity. Generally, synthetic or natural heterocyclic compounds have been investigated in detail as a scaffold for cancer therapeutics. Among them, indole, owing to its unique physiochemical and biological properties, provides a promising platform for the development of pharmacophores for drug development against cancer, acting via various mechanisms. Till now, several indole-based derivatives have been identified as anti-cancer agents, which are either being used in clinics or are in various phases of clinical trials, suggesting their importance in anti-cancer drug development. These anti-cancer drugs have been classified into different classes depending on their mechanism of action. For example, histone deacetylase inhibitors (HDAC inhibitors), silent mating type information regulation 2 homolog (SIRT) inhibitors, tubulin inhibitors, proviral insertion site in Moloney murine leukemia virus (Pim) inhibitors, DNA Topoisomerase inhibitors, and kinase inhibitors. In this review, the author's approach is to compile the recent developments on indole-based anti-cancer drugs and provide insight into the respective structureactivity relationships (SARs) of the compounds. We hope the review will provide a thorough understanding to the reader and guide to developing novel and potent indole-based anticancer agents against drug-sensitive and drug-resistant cancer in the future.

Effect of vorinostat on protein expression in vitro and in vivo following mRNA lipoplex administration.

Previously, we demonstrated that cationic liposomes comprised of N-hexadecyl-N,N-dimethylhexadecan-1-aminium bromide, 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine and poly(ethylene glycol) cholesteryl ether induced substantial protein expression both in vitro and in vivo following the administration of mRNA/cationic liposome complexes (mRNA lipoplexes). The present study evaluated the effect of vorinostat, a histone deacetylase inhibitor, on protein expression levels in vitro and in vivo following the administration of mRNA lipoplexes. The half-maximal inhibitory concentration (IC50) values of vorinostat for human cervical carcinoma HeLa and human liver cancer HepG2 cells were determined to be 7.8 and 2.6 µM, respectively, following a 24 h incubation period. Treatment with 1 µM vorinostat resulted in a 2.7-fold increase in luciferase (Luc) activity for HeLa cells and a 1.6-fold increase for HepG2 cells at 24 h post-transfection with firefly Luc (FLuc) mRNA lipoplexes compared with untreated cells. However, treatment with 10 µM vorinostat decreased Luc activity compared with treatment with 1 µM vorinostat. Intravenous injection of Cy5-labeled mRNA lipoplexes into mice resulted in mRNA accumulation primarily in the lungs; however, co-injection with vorinostat at doses of 5 or 25 mg/kg resulted in mRNA accumulation in both the lungs and liver. Furthermore, intravenous injection of FLuc mRNA lipoplexes resulted in high Luc activity in both the lungs and spleen. Nevertheless, co-injection with vorinostat slightly decreased Luc activity in the lungs but not in the spleen. These findings indicated that vorinostat enhances in vitro protein expression from transfected mRNA after treatment with a lower concentration of IC50; however, it does not largely affect in vivo protein expression from the transfected mRNA.

Givinostat: First Approval.

Givinostat (DUVYZAT™), an orally available histone deacetylase inhibitor, is being developed by Italfarmaco for the treatment of muscular dystrophy and polycythemia vera. Givinostat received its first approval on 21 March 2024, in the USA, for the treatment of Duchenne muscular dystrophy (DMD) in patients 6 years of age and older. Approval was based on the results of the multinational phase III EPIDYS trial, in which givinostat recipients showed less decline than placebo recipients in the time taken to perform a functional task. Givinostat represents the first nonsteroidal treatment for DMD to be approved for use in patients irrespective of the specific genetic variant underlying their disease. Givinostat is available as an oral suspension to be administered twice daily with food. The recommended dosage is based on the body weight of the patient. In the EU, regulatory review of givinostat in DMD is currently underway. This article summarizes the milestones in the development of givinostat leading to this first approval for DMD.

Synergistic drug interactions of the histone deacetylase inhibitor givinostat (ITF2357) in CRLF2-rearranged pediatric B-cell precursor acute lymphoblastic leukemia identified by high-throughput drug screening

Combining multiple drugs broadens the window of therapeutic opportunities and is crucial for diseases that are currently lacking fully curative treatments. A powerful emerging tool for selecting effective drugs and combinations is the high-throughput drug screening (HTP). The histone deacetylase inhibitor (HDACi) givinostat (ITF2357) has been shown to act effectively against CRLF2-rearranged pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL), a subtype characterized by poor outcome and enriched in children with Down Syndrome, very fragile patients with a high susceptibility to treatment-related toxicity. The aim of this study is to investigate possible synergies with givinostat for these difficult-to-treat patients by performing HTP screening with a library of 174 drugs, either approved or in preclinical studies. By applying this approach to the CRLF2-r MHH-CALL-4 cell line, we identified 19 compounds with higher sensitivity in combination with givinostat compared to the single treatments. Next, the synergy between givinostat and the promising candidates was further validated in CRLF2r cell lines with a broad matrix of concentrations. The combinations with trametinib (MEKi) or venetoclax (BCL2i) were found to be the most effective and with the greatest synergy across three metrics (ZIP, HAS, Bliss). Their efficacy was confirmed in primary blasts treated ex vivo at concentration ranges with a safe profile on healthy cells. Finally, we described givinostat-induced modifications in gene expression of MAPK and BCL-2 family members, supporting the observed synergistic interactions. Overall, our study represents a model of drug repurposing strategy using HTP screening for identifying synergistic, efficient, and safe drug combinations.

Cantharidin overcomes IL-2Rα signaling-mediated vorinostat resistance in cutaneous T-cell lymphoma through reactive oxygen species

BackgroundVorinostat (SAHA) is a histone deacetylase inhibitor that has shown clinical efficacy against advanced cutaneous T-cell lymphoma (CTCL). However, only a subset of patients with CTCL (30–35%) respond to SAHA...

Mocetinostat as a Novel Selective Histone Deacetylase Inhibitor in the Promotion of Apoptosis in glioblastoma Cell Line C6 and T98G

Abstract Background: Histone deacetylase (HDAC) enzymes play a crucial role in regulating gene expression and epigenetic alterations in cancer cells. Mocetinostat (MGCD0103) is a novel, isotype-selective HDAC inhibitor that targets Class I (HDAC1, 2, 3, and 8) and Class IV (HDAC11) enzymes. It has been approved for the use in phase II trials for Hodgkin’s lymphoma. Methods: In this study, the glioblastoma cell (GBM) lines T98G and C6 were treated with different concentrations of MGCD0103 (0.0, 0.5, 1.0, 1.5, 2.0, and 2.5 μM). Western blot analysis was used to evaluate protein expression and flow cytometry was employed to assess apoptosis. Results: The results demonstrated that MGCD0103 exerts multiple anti-cancer activities in GBMs. MGCD0103 modulated key signaling pathways, including inhibition of the Phosphatidylinositol 3- kinase (PI3K)/protein kinase B mechanism pathway and suppression of HDAC1 enzyme activity. High doses of MGCD0103 significantly induced apoptosis and suppressed cell proliferation by upregulating the pro-apoptotic protein Bcl-2-associated protein x and downregulating the anti-apoptotic proteins BH3 Interacting Domain Death Agonist and B-cell leukemia/lymphoma 2 protein. In addition, MGCD0103 treatment upregulated the expression of the tumor-suppressor gene and downregulated the E2F1 transcription factor. Furthermore, MGCD0103 facilitated cell differentiation by activating the glial fibrillary acidic protein Glial Fibrillary acidic protein (GFAP) as distinguish marker of astrocytes, and suppressing the undifferentiation markers Inhibitor of Deoxyribonucleic acid binding 2 and N-Myc proto-oncogene protein. Conclusion: This research suggests that MGCD0103 is a promising drug for inhibiting the proliferation, invasion, and migration of GBMs. The findings also provide new insights into the ability of MGCD0103 to induce differentiation in GBMs. Overall, these results indicate that MGCD0103 could be a potent therapeutic agent for the target of glioblastoma.

A Novel Class I HDAC Inhibitor, AW01178, Inhibits Epithelial-Mesenchymal Transition and Metastasis of Breast Cancer.

Epithelial-mesenchymal transition (EMT) refers to the transformation of polar epithelial cells into motile mesenchymal cells under specific physiological or pathological conditions, thus promoting the metastasis of cancer cells. Epithelial cadherin (E-cadherin) is a protein that plays an important role in the acquisition of tumor cell motility and serves as a key EMT epithelial marker. In the present study, AW01178, a small-molecule compound with potential therapeutic efficacy, was identified via in-cell Western high-throughput screening technology using E-cadherin as the target. The compound induced the upregulation of E-cadherin at both mRNA and protein levels and inhibited the EMT of breast cancer cells in vitro as well as metastasis in vivo. Mechanistically, AW01178 is a novel benzacetamide histone deacetylase inhibitor (HDACi) mainly targeting class I histone deacetylases. AW01178 promoted the transcription and expression of E-cadherin through enhancing the acetylation level of histone H3 in the E-cadherin promoter region, thereby inhibiting the metastasis of breast cancer cells. The collective findings support the potential utility of the novel HDACi compound identified in this study, AW01178, as a therapeutic drug for breast cancer and highlight its value for the future development of HDACi structures as anticancer drugs.

Selective inhibition of HDAC6 by N-acylhydrazone derivative reduces the proliferation and induces senescence in carcinoma hepatocellular cells

Hepatocellular carcinoma (HCC) is a significant contributor to cancer-related deaths globally. Systemic therapy is the only treatment option for HCC at an advanced stage, with limited therapeutic response. In this study, we evaluated the antitumor potential of four N-acylhydrazone (NAH) derivatives, namely LASSBio-1909, 1911, 1935, and 1936, on HCC cell lines. We have previously demonstrated that the aforementioned NAH derivatives selectively inhibit histone deacetylase 6 (HDAC6) in lung cancer cells, but their effects on HCC cells have not been explored. Thus, the present study aimed to evaluate the effects of NAH derivatives on the proliferative behavior of HCC cells. LASSBio-1911 was the most cytotoxic compound against HCC cells, however its effects were minimal on normal cells. Our results showed that LASSBio-1911 inhibited HDAC6 in HCC cells leading to cell cycle arrest and decreased cell proliferation. There was also an increase in the frequency of cells in mitosis onset, which was associated with disturbing mitotic spindle formation. These events were accompanied by elevated levels of CDKN1A mRNA, accumulation of CCNB1 protein, and sustained ERK1 phosphorylation. Furthermore, LASSBio-1911 induced DNA damage, resulting in senescence and/or apoptosis. Our findings indicate that selective inhibition of HDAC6 may provide an effective therapeutic strategy for the treatment of advanced HCC, including tumor subtypes with integrated viral genome. Further, in vivo studies are required to validate the antitumor effect of LASSBio-1911 on liver cancer.

Histone deacetylase inhibition mitigates cognitive deficits and astrocyte dysfunction induced by amyloid-β (Aβ) oligomers.

Inhibitors of histone deacetylases (iHDACs) are promising drugs for neurodegenerative diseases. We have evaluated the therapeutic potential of the new iHDAC LASSBio-1911 in Aβ oligomer (AβO) toxicity models and astrocytes, key players in neuroinflammation and Alzheimer's disease (AD). Astrocyte phenotype and synapse density were evaluated by flow cytometry, Western blotting, immunofluorescence and qPCR, in vitro and in mice. Cognitive function was evaluated by behavioural assays using a mouse model of intracerebroventricular infusion of AβO. LASSBio-1911 modulates reactivity and synaptogenic potential of cultured astrocytes and improves synaptic markers in cultured neurons and in mice. It prevents AβO-triggered astrocytic reactivity in mice and enhances the neuroprotective potential of astrocytes. LASSBio-1911 improves behavioural performance and rescues synaptic and memory function in AβO-infused mice. These results contribute to unveiling the mechanisms underlying astrocyte role in AD and provide the rationale for using astrocytes as targets to new drugs for AD.