Histone Deacetylase Inhibitor Research Articles

The Impact of Alcohol-Induced Epigenetic Modifications in the Treatment of Alcohol use Disorders.

Alcohol use disorders are responsible for 5.9% of all death annually and 5.1% of the global disease burden. It has been suggested that alcohol abuse can modify gene expression through epigenetic processes, namely DNA and histone methylation, histone acetylation, and microRNA expression. The alcohol influence on epigenetic mechanisms leads to molecular adaptation of a wide number of brain circuits, including the hypothalamus-hypophysis-adrenal axis, the prefrontal cortex, the mesolimbic-dopamine pathways and the endogenous opioid pathways. Epigenetic regulation represents an important level of alcohol-induced molecular adaptation in the brain. It has been demonstrated that acute and chronic alcohol exposure can induce opposite modifications in epigenetic mechanisms: acute alcohol exposure increases histone acetylation, decreases histone methylation and inhibits DNA methyltransferase activity, while chronic alcohol exposure induces hypermethylation of DNA. Some studies investigated the chromatin status during the withdrawal period and the craving period and showed that craving was associated with low methylation status, while the withdrawal period was associated with elevated activity of histone deacetylase and decreased histone acetylation. Given the effects exerted by ethanol consumption on epigenetic mechanisms, chromatin structure modifiers, such as histone deacetylase inhibitors and DNA methyltransferase inhibitors, might represent a new potential strategy to treat alcohol use disorder. Further investigations on molecular modifications induced by ethanol might be helpful to develop new therapies for alcoholism and drug addiction targeting epigenetic processes.

Autoimmune disease: a view of epigenetics and therapeutic targeting

Autoimmune diseases comprise a large group of conditions characterized by a complex pathogenesis and significant heterogeneity in their clinical manifestations. Advances in sequencing technology have revealed that in addition to genetic susceptibility, various epigenetic mechanisms including DNA methylation and histone modification play critical roles in disease development. The emerging field of epigenetics has provided new perspectives on the pathogenesis and development of autoimmune diseases. Aberrant epigenetic modifications can be used as biomarkers for disease diagnosis and prognosis. Exploration of human epigenetic profiles revealed that patients with autoimmune diseases exhibit markedly altered DNA methylation profiles compared with healthy individuals. Targeted cutting-edge epigenetic therapies are emerging. For example, DNA methylation inhibitors can rectify methylation dysregulation and relieve patients. Histone deacetylase inhibitors such as vorinostat can affect chromatin accessibility and further regulate gene expression, and have been used in treating hematological malignancies. Epigenetic therapies have opened new avenues for the precise treatment of autoimmune diseases and offer new opportunities for improved therapeutic outcomes. Our review can aid in comprehensively elucidation of the mechanisms of autoimmune diseases and development of new targeted therapies that ultimately benefit patients with these conditions.

The Impact of the Histone Deacetylase Inhibitor—Sodium Butyrate on Complement-Mediated Synapse Loss in a Rat Model of Neonatal Hypoxia–Ischemia

AbstractPerinatal asphyxia is one of the most important causes of morbidity and mortality in newborns. One of the key pathogenic factors in hypoxic-ischemic (HI) brain injury is the inflammatory reaction including complement system activation. Over-activated complement stimulates cells to release inflammatory molecules and is involved in the post-ischemic degradation of synaptic connections. On the other hand, complement is also involved in regenerative processes. The histone deacetylase inhibitor (HDACi)—sodium butyrate (SB)—provides reduction of inflammation by decreasing the expression of the proinflammatory factors. The main purpose of this study was to examine the effect of SB treatment on complement activation and synapse elimination after HI. Neonatal HI was induced in Wistar rats pups by unilateral ligation of the common carotid artery followed by 60-min hypoxia (7.6% O2). SB (300 mg/kg) was administered on a 5-day regimen. Our study has shown decreased levels of synapsin I, synaptophysin, and PSD-95 in the hypoxic-ischemic hemisphere, indicating synaptic loss after neonatal HI. Transmission electron microscopy revealed injury of the synaptic structures in the brain after HI. SB treatment increased the level of the synaptic proteins, improved tissue ultrastructure, and reduced degradation of the synapses. Neonatal HI induced mRNA expression of the complement C1q, C3, C5, and C9, and their receptors C3aR and C5aR. The effect of SB was different depending on the time after induction of hypoxic-ischemic damage. Our study demonstrated that neuroprotective effect of SB may be related to the modulation of complement activity after HI brain injury.

Spirotetrahydroisoquinoline-Based Histone Deacetylase Inhibitors as New Antifibrotic Agents: Biological Evaluation in Human Fibroblasts from Bronchoalveolar Lavages of Idiopathic Pulmonary Fibrosis Patients

Spirotetrahydroisoquinoline-Based Histone Deacetylase Inhibitors as New Antifibrotic Agents: Biological Evaluation in Human Fibroblasts from Bronchoalveolar Lavages of Idiopathic Pulmonary Fibrosis Patients

Drug prioritization identifies panobinostat as a tailored treatment element for patients with metastatic hepatoblastoma

Abstract Background Patients with metastatic hepatoblastoma are treated with severely toxic first-line chemotherapies in combination with surgery. Yet, inadequate response of lung metastases to neo-adjuvant chemotherapy still compromises patient outcomes making new treatment strategies, tailored to more efficient lung clearance, mandatory. Methods We harnessed a comprehensive patient-derived xenograft platform and a variety of in vitro and in vivo assays to establish the preclinical and biological rationale for a new drug for patients with metastatic hepatoblastoma. Results The testing of a library of established drugs on patient-derived xenografts identified histone deacetylase inhibitors, most notably panobinostat, to be highly efficacious on hepatoblastoma cells, as compared to non-cancerous cells. Molecularly, the anti-tumor effect of panobinostat is mediated by posttranslational obstruction of the MYC oncoprotein as a result of dual specificity phosphatase 1 upregulation, thereby leading to growth inhibition and programmed cell death. Of clinical importance, upregulation of the MYC target gene nucleophosmin 1 is indicative of response to panobinostat and associated with metastatic disease in patients with hepatoblastoma. The combination of panobinostat with the current SIOPEL 4 induction protocol, consisting of cisplatin and doxorubicin, revealed high synergies already at low nanomolar levels. The simulation of a clinical trial, with this combination therapy, in patient-derived xenograft models, and ultimately heterotypic lung metastasis mimics clearly underscored the potency of this approach. Conclusion Integrated studies define MYC inhibition by panobinostat as a novel treatment element to be introduced into the therapeutic strategy for patients with metastatic hepatoblastoma.

EXTH-47. ENHANCING GD2.CART THERAPY FOR DIFFUSE MIDLINE GLIOMA WITH LSD1 AND HDAC INHIBITORS

Abstract Chimeric antigen receptor T cells against the glycolipid GD2 (GD2.CARTs) are showing promise in diffuse midline glioma (DMG) but are not yet curative. Since low target antigen expression is one potential mechanism by which tumor cells can escape CART therapy, we profiled GD2 expression levels on 9 different H3K27M-mutant DMG cell lines using flow cytometry. This analysis shows that only 5 of the 9 cell lines exhibit high GD2 expression while the remaining 4 lines have low GD2-expressing cells. When treating these cell lines with GD2.CARTs in co-culture assays and xenograft mice, we find that low GD2 expression on DMG cells correlates with tumor cell escape from GD2.CARTs and therapeutic resistance in vivo. Our lab previously found that simultaneous inhibition of histone deacetylases (HDACs) and lysine-demethylase 1 (LSD1) in DMG cells causes synergistic increases in gene expression and tumor cell death. Previous studies in neuroblastoma also demonstrate that HDAC inhibitor (HDACi) treatment can increase GD2 on tumor cells and improve targeting by GD2.CARTs. We therefore decided to assess whether treating GD2-low DMG cell lines with combinations of LSD1 inhibitors (LSD1i) and HDACi improves DMG response to GD2.CARTs. Immunofluorescence and flow cytometric analyses show that GD2 expression is increased on LSD1i+HDACi-treated GD2-low DMG cells and that there is enhanced tumor cell targeting by GD2.CARTs in subsequent co-culture assays. Treating mice transplanted with GD2-low DMG cells with LSD1i+HDACi followed by intravenous GD2.CART infusion also led to reduced tumor growth. These results suggest that LSD1i+HDACi pre-treatment may provide a way to improve DMG patient responses to GD2.CART therapy by increasing target antigen expression.

TMET-22. OVERCOMING RESISTANCE: PANOBINOSTAT SENSITIZES 2DG-RESISTANT PEDIATRIC HIGH-GRADE GLIOMAS WITH H3.3 K27M/G34R MUTATIONS TO APOPTOSIS

Abstract BACKGROUND Pediatric high-grade gliomas (pHGG) harboring H3.3 K27M/G34R mutations present formidable challenges in treatment due to their aggressiveness and resistance to standard chemotherapy. Our preliminary investigations have shown promising results, indicating that combining 2-deoxyglucose (2DG), a glycolytic inhibitor, with DNA-damaging agents synergistically inhibits pHGG growth. However, prolonged exposure to 2DG induces resistance, necessitating the exploration of alternative therapies. This study aims to investigate the potential of panobinostat, a histone deacetylase inhibitor, in sensitizing 2DG-resistant pHGG with H3.3 K27M/G34R mutations to apoptosis. METHODS Transcriptomic analysis via Illumina NovaSeq 6000 and metabolomic profiling employing Liquid Chromatography-High-Resolution Mass Spectrometry was used to delineate the molecular landscape of naive and 2DG-resistant pHGG cell lines. Functional assays, including the Agilent Seahorse Mito Stress Test and flow cytometry, assessed bioenergetics and mitochondrial dynamics. Intracellular NAD+ and NADH levels were quantified utilizing NAD+/NADH Glo assays, while apoptotic markers and metabolic stress were measured using the Annexin V-FITC Conjugates for Apoptosis Detection kit and western blot. RESULTS Comparative analysis revealed increased transketolase activity in 2DG-resistant cells, augmenting the interaction between the pentose phosphate pathway and glycolysis, resulting in elevated levels of NADPH and ATP. Additionally, these resistant cells displayed enhanced reliance on mitochondrial energy metabolism, as evidenced by substantial increases in mitochondrial membrane potential and mass, coupled with elevated NAD+ levels. Subsequent treatment with panobinostat induced a significant decrease in NAD+ biosynthesis and ATP generation. Furthermore, this intervention triggered the upregulation of pro-apoptotic BCL-2 family proteins, particularly BAX and BAK, concomitant with a notable reduction in mitochondrial membrane potential and the accumulation of reactive oxygen species. Consequently, heightened caspase-3 activity ensued, leading to significantly elevated cell death rates in 2DG-resistant gliomas. CONCLUSION Our findings highlight panobinostat as a promising therapy to resensitize 2DG-resistant pHGG cells to apoptosis, offering hope for treating these aggressive tumors with H3.3 K27M/G34R mutations.

TMIC-11. THE EFFECTIVENESS OF VALPROIC ACID IN COMBINATION WITH TEMOZOLOMIDE FOR TREATMENT OF HIGH-GRADE GLIOMAS: A SYSTEMATIC REVIEW AND META-ANALYSIS

Abstract BACKGROUND High-grade gliomas (HGGs) rapidly progress with a high recurrence rate and poor prognosis despite standard multimodal treatment. Valproic acid (VPA), a histone deacetylase inhibitor, sensitizes HGG to radiochemotherapy along with having potential anti-cancer mechanisms and augmenting the growth inhibitory effect of Temozolomide (TMZ). This study explores the effectiveness of VPA in combination with TMZ for treating patients with HGG. METHODS A comprehensive literature search was performed on PubMed, Scopus, Embase, and Web of Science databases and identified relevant studies (case-control, cohort, RCTs) comparing the synergistic effect of VPA during TMZ to TMZ without VPA. We investigated median overall survival (OS), Progression-free survival (PFS), and baseline MGMT methylation status to evaluate this relationship. RESULTS Our systematic review encompassed 9 studies involving 4,097 patients with HGGs (seven cohorts, one case-control, and one RCT). The pooled analysis of median OS demonstrated no statistical significance difference between VPA during TMZ and TMZ alone (MD=-3.97; 95%CI=-8.43-0.49; p=0.08). However, sub-analysis showed a statistically significant effect in studies with sample size <100 (MD=-5.06; 95%CI=-9.32,-0.80; p<0.02), and 100-200 (MD=-7.07; 95%CI=-13.15,-1.00; p<0.02), and those conducted before 2015 (MD=-5.62, 95%CI=-9.08,-2.17, p<0.01). On meta-regression analysis, no statistical significance (RC=0.82,95% CI=0.39,-2.03, p=0.18) was observed, indicating that the study year is not associated with the intervention. A separate analysis of 3 studies also showed no significant variance in the baseline percentage of patients without MGMT methylation (log OR=-0.35, 95%CI=-1.02,-0.32, p=0.30) when administering VPA during TMZ treatment (n=67) compared to TMZ alone (n=409). Additionally, VPA during TMZ does not significantly affect PFS (MD=-3.54; 95% CI=-10.18-3.10, p=0.30) compared to TMZ alone. CONCLUSIONS The concurrent use of VPA with TMZ shows no significant effect on OS and PFS, nor does it show any variance in the baseline MGMT methylation status compared to TMZ alone. However, smaller sample sizes show a significant effect. Thus, our findings emphasize the imperative for additional research aimed at refining clinical outcomes.

Macrophages producing chondroitin sulfate proteoglycan‐4 induce neuro‐cardiac junction impairment in Duchenne muscular dystrophy

AbstractDuchenne muscular dystrophy (DMD) is caused by the absence of the full form of the dystrophin protein, which is essential for maintaining the structural integrity of muscle cells, including those in the heart and respiratory system. Despite progress in understanding the molecular mechanisms associated with DMD, myocardial insufficiency persists as the primary cause of mortality, and existing therapeutic strategies remain limited. This study investigates the hypothesis that a dysregulation of the biological communication between infiltrating macrophages (MPs) and neurocardiac junctions exists in dystrophic cardiac tissue. In a mouse model of DMD (mdx), this phenomenon is influenced by the over‐release of chondroitin sulfate proteoglycan‐4 (CSPG4), a key inhibitor of nerve sprouting and a modulator of the neural function, by MPs infiltrating the cardiac tissue and associated with dilated cardiomyopathy, a hallmark of DMD. Givinostat, the histone deacetylase inhibitor under current development as a clinical treatment for DMD, is effective at both restoring a physiological microenvironment at the neuro‐cardiac junction and cardiac function in mdx mice in addition to a reduction in cardiac fibrosis, MP‐mediated inflammation, and tissue CSPG4 content. This study provides novel insight into the pathophysiology of DMD in the heart, identifying potential new biological targets. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

CSIG-09. BEYOND SINGLE AGENTS: EXPLORING THE POTENTIAL OF ABEMACICLIB IN COMBINATION WITH PANOBINOSTAT FOR IMPROVED GLIOMA TREATMENT

Abstract BACKGROUND Glioblastoma is the most common primary central nervous system tumour with a median survival of less than 15 months. Addressing the underlying redundant, and converging signaling pathways necessitates the utilization of small molecule inhibitors capable of simultaneous targeting and inhibition. In glioma, the aberrant CDK4/6-Rb pathway dysregulation resulting in disruption of cell cycle checkpoint progression can lead to uncontrolled cell division, a hallmark of cancer. The neuro-pharmacokinetics of abemaciclib, a Cyclin-dependent kinase inhibitor, is being currently investigated in phase 1 clinical trials by National Cancer Institue, [NCT05413304]. The importance of panobinostat as a Histone deacetylase inhibitor and potentiating the effects of various small molecular inhibitors in published literature is paramount. This study is based on investigating ways to overcome resistance by exploring the synergistic cytotoxic effects of abemaciclib in combination with panobinostat in glioma. METHODS We investigated the antiproliferative effects of abemaciclib and panobinostat on glioma cells using an MTS cell proliferation assay. Inhibitor combination analysis was done using, SYNERGYFINDER via zip-model. Flow cytometry with Annexin V staining further assessed cell death and apoptosis induced. RESULTS The antiproliferative effects of abemaciclib, alone and in combination with panobinostat, in pediatric lines (KNS 42, SJG2), and adult human glioblastoma line, SF188 exhibited lower IC50 as compared to adult high grade glioma lines (LN 18, LNZ 308). Synergy analysis revealed a strong cytotoxic effect in KNS 42 and SF 188 cells treated with the combination. Flow cytometric analysis indicated that the combination therapy induced significant cell death only in a subset of cell lines- KNS 42 and SF 188, suggesting underlying genetic heterogeneity influences treatment response, warranting further mechanistic studies. CONCLUSION Combination therapies using abemaciclib and panobinostat, targeting CDK4/6 and histone deacetylation pathways, show promise against aggressive and treatment-resistant gliomas. Further investigation into these combination approaches is crucial to understand resistant mechanisms, optimize efficacy, and establish their clinical efficacy for improving glioma patient outcomes.

Aromatic Amino Acid Hydroxylases as Off-Targets of Histone Deacetylase Inhibitors

Aromatic Amino Acid Hydroxylases as Off-Targets of Histone Deacetylase Inhibitors

Panobinostat Attenuates Experimental Autoimmune Encephalomyelitis in Mice via Suppressing Oxidative Stress-Related Neuroinflammation and Mitochondrial Dysfunction

Multiple sclerosis (MS) is an autoimmune disease mediated by T helper cells, which is characterized by neuroinflammation, axonal or neuronal loss, demyelination, and astrocytic gliosis. Histone deacetylase inhibitors (HDACis) are noted for their roles in easing inflammatory conditions and suppressing the immune response. Panobinostat, an HDACi, is now being used in treating multiple myeloma. Nevertheless, the effect of panobinostat on autoimmune diseases remains largely unclear. Thus, our research endeavored to determine if the administration of panobinostat could prevent experimental autoimmune encephalomyelitis (EAE) in mice, one of the most commonly used animal models of MS, and further explored the underlying mechanisms. The EAE mice were generated and then administered continuously with panobinostat at a dosage of 30 mg/kg for 16 days. The results indicated that panobinostat markedly alleviated the clinical symptoms of EAE mice, inhibiting demyelination and loss of oligodendrocytes in the central nervous system (CNS). Moreover, panobinostat decreased inflammation and the activation of microglia and astrocytes in the spinal cords of EAE mice. Mechanistically, treatment with panobinosat significantly suppressed M1 microglial polarization by blocking the activation of toll-like receptor 2 (TLR2)/myeloid differentiation factor 88 (MyD88)/interferon regulatory factor 5 (IRF5) pathway. Additionally, panobinostat inhibited mitochondrial dysfunction and reduced oxidative stress in the spinal cords of EAE mice. In conclusion, our findings reveal that panobinostat significantly ameliorates experimental autoimmune encephalomyelitis in mice by inhibiting oxidative stress-linked neuroinflammation and mitochondrial dysfunction.

The Two Faces of HDAC3: Neuroinflammation in Disease and Neuroprotection in Recovery.

Histone deacetylase 3 (HDAC3) is a critical regulator of gene expression, influencing a variety of cellular processes in the central nervous system. As such, dysfunction of this enzyme may serve as a key driver in the pathophysiology of various neuropsychiatric disorders and neurodegenerative diseases. HDAC3 plays a crucial role in regulating neuroinflammation, and is now widely recognized as a major contributor to neurological conditions, as well as in promoting neuroprotective recovery following brain injury, hemorrhage and stroke. Emerging evidence suggests that pharmacological inhibition of HDAC3 can mitigate behavioral and neuroimmune deficits in various brain diseases and disorders, offering a promising therapeutic strategy. Understanding HDAC3 in the healthy brain lays the necessary foundation to define and resolve its dysfunction in a disease state. This review explores the mechanisms of HDAC3 in various cell types and its involvement in disease pathology, emphasizing the potential of HDAC3 inhibition to address neuroimmune, gene expression and behavioral deficits in a range of neurodegenerative and neuropsychiatric conditions.

DNA Methylation and Histone Acetylation Contribute to the Maintenance of LTP in the Withdrawal Behavior Interneurons in Terrestrial Snails

Accumulated data indicate that epigenetic regulations, including histone modifications and DNA methylation, are important means for adjusting the expression of genes in response to various stimuli. In contrast to the success in studying the role of DNA methylation in laboratory rodents, the role of DNA methylation in the terrestrial snail Helix lucorum has been studied only in behavioral experiments. This prompted us to further investigate the role of DNA methylation and the interaction between DNA methylation and histone acetylation in the mechanisms of neuroplasticity in terrestrial snails using in vitro experiments. Dysregulation of DNA methylation by the DNMT inhibitor RG108 significantly suppressed the long-term potentiation (LTP) of synaptic inputs in identified neurons. We then tested whether the RG108-induced weakening of potentiation can be reversed under co-application of histone deacetylase inhibitors sodium butyrate or trichostatin A. It was found that increased histone acetylation significantly compensated for RG108-induced LTP deficiency. These data bring important insights into the functional role of DNA methylation as an important regulatory mechanism and a necessary condition for the development and maintenance of long-term synaptic changes in withdrawal interneurons of terrestrial snails. Moreover, these results support the idea of the interaction of DNA methylation and histone acetylation in the epigenetic regulation of synaptic plasticity.

Epigenetic Regulation of Immune Cells in Health and Disease: A Comprehensive Review

Epigenetic regulation plays a crucial role in the development, differentiation, and function of immune cells. Mechanisms such as DNA methylation, histone modifications, chromatin remodeling, and non-coding RNA interactions dynamically shape gene expression, enabling immune cells to adapt to environmental stimuli and mediate appropriate immune responses. Aberrant epigenetic regulation is implicated in a range of diseases, including autoimmune disorders, cancer, and chronic inflammatory conditions. In autoimmune diseases, such as systemic lupus erythematosus and rheumatoid arthritis, altered DNA methylation and histone modifications contribute to immune dysregulation and tissue damage. In cancer, immune cells in the tumor microenvironment often exhibit epigenetic changes that facilitate immune evasion. Emerging therapeutic strategies targeting epigenetic pathways, including DNA methyltransferase inhibitors, histone deacetylase inhibitors, and CRISPR-based epigenome editing, offer promising approaches for treating immune-mediated diseases. This review provides a comprehensive overview of the epigenetic mechanisms governing immune cell behavior, their dysregulation in disease, and the potential of epigenetic therapies to restore immune homeostasis and improve patient outcomes. Keywords: Epigenetics, immune cells, DNA methylation, histone modifications, non-coding RNAs, autoimmune diseases, immunotherapy

Molecular Imaging Reveals Antineuroinflammatory Effects of HDAC6 Inhibition in Stroke Models.

Ischemic stroke is a devastating disease that causes neuronal death, neuroinflammation, and other cerebral damage. However, effective therapeutic strategies for ischemic stroke are still lacking. Histone deacetylase 6 (HDAC6) has been implicated in the pathogenesis of ischemic stroke, and the pharmacological inhibition of HDAC6 has shown promising neuroprotective effects. In this study, we utilized positron emission tomography (PET) imaging with the HDAC6-specific radioligand [18F]PB118 to investigate the dynamic changes of HDAC6 expression in the brain after ischemic injury. The results revealed a significant decline in [18F]PB118 uptake in the ipsilateral hemisphere on the first day after ischemia, followed by a gradual increase on days 4 and 7. To evaluate the therapeutic potential of HDAC6 inhibitors, we developed a novel brain-permeable and potent HDAC6 inhibitor, PB131, and assessed its neuroprotective effects in an ischemic stroke mouse model. PET imaging studies demonstrated that PB131 treatment alleviated the decline in [18F]PB118 uptake and reduced the infarct size in middle cerebral artery occlusion mice. Furthermore, PET imaging with the TSPO-specific radioligand [18F]FEPPA revealed that PB131 significantly suppressed neuroinflammation in the ischemic brain. These findings provide insights into the dynamic changes of HDAC6 in ischemic stroke and the potential of HDAC6 inhibitors as novel therapeutic agents for this condition.

Discovery and Development of HDAC Inhibitors: Approaches for the Treatment of Cancer a Mini-review.

Histone deacetylase (HDAC) inhibitors have emerged as promising cancer therapeutics due to their ability to induce differentiation, cell cycle arrest, and apoptosis in cancer cells. In the present review, we have described the systemic discovery and development of HDAC inhibitors. Researchers across the globe have identified various small molecules like benzo[d][1,3]dioxol derivatives, belinostat analogs, pyrazine derivatives, quinazolin-4-one-based derivatives, 2,4-imidazolinedione derivatives, acridine hydroxamic acid derivatives, coumarin derivatives, tetrahydroisoquinoline derivatives, thiazole-5-carboxamide, salicylamide derivatives, β-peptoid-capped HDAC inhibitors, quinazoline derivatives, benzimidazole and benzothiazole derivatives, and β- elemene scaffold containing HDAC inhibitors. Most of the scaffolds have shown attractive IC50 (μM) in various cell lines like HDAC1, HDAC2, HDAC6, PI3K, HeLa, MDA-MB-231, MCF-10A, MCF-7, U937, K562 and Bcr-Abl cell lines.

Updated Survival Follow-Up for Phase Ib Trial of the Histone Deacetylase Inhibitor Abexinostat With Pazopanib in Patients With Solid Tumor Malignancies.

Histone deacetylase (HDAC) inhibition downregulates hypoxia-inducible factor-1α and modulates multiple metabolomic pathways relevant in cancer. Here we report a potential novel biomarker to predict exceptional responders (>3 years) in patients receiving HDAC and vascular endothelial growth factor (VEGF) inhibition. Patients with solid tumor malignancies were enrolled in this phase Ib trial of abexinostat (4/7 ×21 days) and pazopanib (28/28 days), with a dose expansion in renal cell carcinoma (RCC). Plasma was analyzed for metabolomics and peripheral blood mononuclear cells (PBMCs) for VEGF and HDAC2 expression levels. Fifty-one patients were enrolled: n = 36 patients in dose escalation and n = 15 in dose expansion. After the initial report in 2017, six patients had remained on study: four with RCC and one each with medullary thyroid and thymic neuroendocrine carcinoma. One patient with RCC remains on treatment for >11 years after progression on five systemic therapies. Overall, the median duration of therapy measured 5.6 (1-133) months. The median duration of therapy in exceptional responders measured 44.1 (39.8-133+) months. The median overall survival in patients with high PBMC HDAC2 expression versus low HDAC2 was 32.3 versus 9.2 months (P = .004) for all patients and 43.3 versus 25.1 months for patients with RCC (P = .09). Exceptional responders had lower kynurenine levels both pre- and post-treatment (P = .002, P < .001, respectively). HDAC2 and kynurenine expression levels were inversely correlated (P = .02). Abexinostat added to pazopanib shows extended tolerability and long-term responses and survival. PBMC HDAC2 levels, the abexinostat target, are relevant predictors of response. In addition, metabolomic assessment points to kynurenine as a predictor for exceptional response to combined VEGF plus HDAC inhibition.

Multicomponent Syntheses Enable the Discovery of Novel Quisinostat-Derived Chemotypes as Histone Deacetylase Inhibitors

In this study, we synthesized and evaluated novel histone deacetylase (HDAC) inhibitors derived from the clinical candidate quisinostat. A library of 16 compounds categorized in three novel chemotypes was rapidly generated using multicomponent reactions (MCRs), enabling efficient structure-activity relationship studies. First, the compounds were evaluated for their activity against the Plasmodium falciparum strains 3D7 and Dd2, the main malaria-causing parasite, identifying compound 18b of the type C series as the most potent. It demonstrated low nanomolar IC50 values (IC50 (3D7) = 0.023 μM; IC50 (Dd2) = 0.047 μM) and high parasite selectivity (SIMRC-5/Pf3D7 > 2174). HDAC inhibition assays confirmed substantial inhibition of the P. falciparum enzyme PfHDAC1 (IC50 = 0.037 μM) as well as of human HDAC1 (IC50 = 0.021 μM) and HDAC6 (IC50 = 0.25 μM). Docking studies suggested distinct binding modes of 18b in P. falciparum and human HDAC1. Additionally, the in vitro anticancer activity was evaluated in Cal27 (head-neck carcinoma), HepG2 (hepatocellular carcinoma), A2780 (ovarian carcinoma), and U87 (glioblastoma) cell lines. Compounds 9b, 9d, and 13f showed potent antiproliferative activity and caspase 3/7 activation, in contrast to 18b. Furthermore, these compounds caused hyperacetylation of histone H3 and α-tubulin, indicating robust cellular target engagement. Overall, in this work we have identified the HDAC inhibitor 18b with selective antiplasmodial and 9b, 9d, and 13f with selective anticancer activities, providing valuable hits for further drug development efforts aimed at creating derivatives with reduced cytotoxicity against non-cancer cells compared to quisinostat.

Combination of multivalent DR5 receptor clustering agonists and histone deacetylase inhibitors for treatment of colon cancer

Death Receptor 5 (DR5) targeted therapies offer significant promise due to their pivotal role in mediating the extrinsic pathway of apoptosis. Despite DR5 overexpression in various malignancies and the potential of tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), clinical implementations of anti-DR5 monoclonal antibodies (mAbs) have been hampered by suboptimal outcomes potentially due to lack of receptor clustering.To address the limitation, we developed N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-based conjugates integrating multiple copies of DR5-targeting peptide (cyclic WDCLDNRIGRRQCVKL; cDR5) to enhance receptor clustering and apoptosis. Three conjugates with variable number of cDR5 were prepared and denoted as PH-cDR5 (high valence), PM-cDR5 (medium valence) and PL-cDR5 (low valence). Our studies in TRAIL-sensitive and resistant cancer cell lines demonstrated that the HPMA copolymer-peptide conjugates (P-cDR5) significantly improved DR5 receptor clustering and induced apoptosis effectively. In TRAIL-sensitive colon cancer cells (COLO205, HCT-116), P-cDR5 showed efficacy comparable to anti-DR5 mAb Drozitumab (DRO), but P-cDR5 outperformed DRO in TRAIL-resistant cells (HT-29), highlighting the importance of efficient receptor clustering. In COLO205 cells PM-cDR5 exhibited an IC50 of 94 pM, while PH-cDR5 had an even lower IC50 of 15 pM (based on cDR5 equivalent concentration), indicating enhanced potency of the multivalent HPMA copolymer-based system with a flexible polymer backbone in comparison with the IC50 for TRAIL at 0.12 nM. Combining P-cDR5 with valproic acid, a histone deacetylase inhibitor, resulted in further enhancement of apoptosis inducing efficacy, along with destabilizing mitochondrial membranes and increased sensitivity of TRAIL-resistant cells. These findings suggest that attaching multiple cDR5 peptides to a flexible water-soluble polymer carrier not only overcomes the limitations of previous designs but also offers a promising avenue for treating resistant cancers, pointing toward the need for further preclinical exploration and validation of this innovative strategy.