ACY-738 / Pfizer, BMS - LARVOL DELTA

HDAC6 Deletion Decreases Pristane-induced Inflammation. (PubMed, Immunohorizons) - "In vitro studies in J774A.1 cells revealed that the selective HDAC6 inhibitor (ACY-738) increased acetylation of NF-κB while increasing Stat1 phosphorylation, which resulted in inducible NO synthase production in LPS/IFN-γ-stimulated cells. Taken together, these results demonstrate that although HDAC6 inhibition may inhibit some inflammatory pathways, others remain unaffected."

Journal • Immunology • Inflammation • Inflammatory Arthritis • Lupus • Systemic Lupus Erythematosus • CD69 • IFNG • ITGAM

HDAC6 inhibition as a mechanism to prevent neurodegeneration in the mSOD1G93A mouse model of ALS. (PubMed, Heliyon) - "This study shows ACY-738 treatment increased acetylation of microtubules in the spinal cord of mSOD1G93A mice, reduced lower motor neuron degeneration in female mice, ameliorated reduction in peripheral nerve axon puncta size, but did not prevent overt motor function decline. The current study also shows peripheral nerve axon puncta size to be partially restored after treatment with riluzole and highlights the importance of co-treatment to measure the potential effects of therapeutics in ALS."

Journal • Preclinical • Amyotrophic Lateral Sclerosis • CNS Disorders

HDAC6 INHIBITOR ACY-738 INDUCES FERRITINOPHAGY-MEDIATED FERROPTOSIS IN LEUKEMIA (EBMT 2024) - "In summary, we provided the evidence that HDAC6 inhibitor ACY-738 inhibited the proliferation and induced ferroptosis in leukemia cells. Mechanistically, ACY-738 induces ferroptosis through promotes NCOA4-mediated ferritinophagy and regulated the SLC7A11-GPX4 axis. ACY-738, identified as a novel ferroptosis inducer, may be effective chemosensitizer that can expand the efficacy and range of chemotherapeutic agents."

Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • Targeted Protein Degradation • GPX4 • NCOA4 • SLC7A11

HDAC6 Inhibition Activates Proteasomes to Modulate the MHC Class I Immunopeptidome and Promote Antimyeloma Immunity (ASH 2023) - "The HTS revealed that the histone deacetylase 6 (HDAC6)-selective inhibitors tubastatin-A, ACY-738 and ACY-1215 increased proteasome activity in a panel of multiple myeloma (MM) cell lines. Proteasome activators also represent a paradigm-shifting approach to overcome mechanisms of immune escape. FDA-approved drugs that increase proteasome activity and boost antigen presentation can now be repositioned as cancer immunotherapeutics to overcome the existing bottlenecks in drug development."

IO biomarker • Tumor mutational burden • Hematological Malignancies • Multiple Myeloma • Oncology • Targeted Protein Degradation • CD8 • SDC1 • TMB • UBB

Effects of HDAC6 Inhibition in ALS mouse models (ALS-MND 2023) - "Our goal is to evaluate the therapeutic potential of ACY-738 with and without the current therapeutic drug, riluzole, in these ALS models. Overall, there were limited protective effects of HDAC6 inhibition with ACY-738 on neurodegeneration in mSOD1-G93A mice. The potential effects of ACY-738 on axonal degeneration and global proteome are currently being further evaluated in the TDP-43 models. Fariha.Kabir@utas.edu.au"

Preclinical • Alzheimer's Disease • Amyotrophic Lateral Sclerosis • CNS Disorders • Oncology • Sarcoma • Solid Tumor • NEFH • TARDBP

HDAC-6 inhibition ameliorates the early neuropathology in a mouse model of Krabbe disease. (PubMed, Front Mol Neurosci) - "ACY-738 was effective in rescuing neuronal defects of Twitcher neurons, stabilizing microtubule dynamics and increasing the axonal transport of mitochondria. Overall, our results support that ACY-738 has a neuroprotective effect in KD and should be considered as an add-on therapy combined with strategies targeting metabolic correction."

Journal • Preclinical

ARIH1 activates STING-mediated T-cell activation and sensitizes tumors to immune checkpoint blockade. (PubMed, Nat Commun) - "Using a high-throughput drug screen, we further identify that ACY738, less cytotoxic than cisplatin, effectively upregulates ARIH1 and activates STING signaling, sensitizing tumors to PD-L1 blockade. Our findings delineate a mechanism that tumors mediate ICB resistance through the loss of ARIH1 and ARIH1-DNA-PKcs-STING signaling and indicate that activating ARIH1 is an effective strategy to improve the efficacy of cancer immunotherapy."

Checkpoint block • Checkpoint inhibition • IO biomarker • Journal • Immune Modulation • Oncology • Targeted Protein Degradation • CGAS • STING • UBR5

Histone Deacetylase Inhibition Regulates Lipid Homeostasis in a Mouse Model of Amyotrophic Lateral Sclerosis. (PubMed, Int J Mol Sci) - "Recently, histone deacetylase (HDAC) inhibition using ACY-738 has been shown to restore metabolic alterations in the spinal cord of a FUS mouse model of ALS, which was accompanied by a beneficial effect on the motor phenotype and survival...Strikingly, HDAC inhibition mitigated lipid homeostasis defects by selectively targeting glycerophospholipid metabolism and reducing cholesteryl esters accumulation. Therefore, our data suggest that HDAC inhibition is a potential new therapeutic strategy to modulate lipid metabolism defects in ALS and potentially other neurodegenerative diseases."

Epigenetic controller • Journal • Preclinical • Amyotrophic Lateral Sclerosis • CNS Disorders • Metabolic Disorders • FUS

[VIRTUAL] Neuronal complexity is attenuated in chronic migraine and restored by HDAC6 inhibition (AHS 2021) - "On day 10, 24h after the final NTG/VEH injection, animals were tested with the HDAC6 inhibitor, ACY-738 (50mg/kg, IP) or vehicle... Our results demonstrate that migraine pathophysiology is associated with disrupted neuronal cytoarchitecture. Furthermore, we show that HDAC6 inhibition and Olcegepant both can effectively reverse cytoarchitectural alterations and reveal a possible mechanism for migraine therapeutics"

CNS Disorders • Depression • Migraine • Pain • Psychiatry

HDAC6 Signaling at Primary Cilia Promotes Proliferation and Restricts Differentiation of Glioma Cells. (PubMed, Cancers (Basel)) - "We found that HDAC6 inhibitors ACY-1215 (1215) and ACY-738 (738) inhibited the proliferation of multiple patient-derived and mouse glioma cells. Surprisingly, overexpressing HDAC6 did not reduce cilia length or the frequency of ciliated glioma cells, suggesting other factors are required to control HDAC6-mediated cilia disassembly in glioma cells. Collectively, our findings suggest that HDAC6 promotes the proliferation of glioma cells through primary cilia."

Journal • Brain Cancer • Glioblastoma • Glioma • Oncology • Solid Tumor • HDAC6

HDAC6 Inhibition Alleviates CLL-Induced T-Cell Dysfunction and Enhances Immune Checkpoint Blockade Efficacy in the Eμ-TCL1 Model. (PubMed, Front Immunol) - "Conclusively, combination treatment with ACY738 augmented the antitumor efficacy of anti-PD-1 and anti-PD-L1 monoclonal antibodies in the Eμ-TCL1 adoptive transfer murine model. These combinatorial antitumor effects coincided with an increased cytotoxic CD8 T-cell phenotype. Taken together, these data highlight a role for HDAC inhibitors in combination with immunotherapy and provides the rationale to investigate HDAC6 inhibition together with immune checkpoint blockade for treatment of CLL patients."

Checkpoint inhibition • Clinical • IO Biomarker • Journal • Chronic Lymphocytic Leukemia • Hematological Malignancies • Immune Modulation • Immunology • Inflammation • Leukemia • Oncology

Selective Histone Deacetylase 6 Inhibition Normalizes B Cell Activation and Germinal Center Formation in a Model of Systemic Lupus Erythematosus. (PubMed, Front Immunol) - "We treated NZB/W lupus mice with the selective HDAC6 inhibitor, ACY-738, for 4 weeks beginning at 20 weeks-of age...Pathway analysis suggested alterations in cellular metabolism might contribute to the normalization of lupus mouse spleen genomic signatures, and this was confirmed by direct measurement of the impact of the HDAC6 inhibitor on metabolic activities of murine spleen cells. Taken together, these studies show HDAC6 inhibition decreases B cell activation signaling pathways and reduces PC differentiation in SLE and suggest that a critical event might be modulation of cellular metabolism."

Journal • Complement-mediated Rare Disorders • Glomerulonephritis • Immunology • Inflammatory Arthritis • Lupus • Lupus Nephritis • Nephrology • Systemic Lupus Erythematosus

HDAC6-selective inhibitors decrease nerve-injury and inflammation-associated mechanical hypersensitivity in mice. (PubMed, Psychopharmacology (Berl)) - "Overall, our findings suggest that inhibition of HDAC6 provides a promising therapeutic avenue for the alleviation of mechanical allodynia associated with peripheral nerve injury and peripheral inflammation."

Journal • Preclinical • Immunology • Inflammation • Neuralgia • Pain • Peripheral Neuropathic Pain

Restoration of histone acetylation ameliorates disease and metabolic abnormalities in a FUS mouse model. (PubMed, Acta Neuropathol Commun) - "At the molecular level, ACY-738 restored global histone acetylation and metabolic gene expression, thereby re-establishing metabolite levels in the spinal cord. Taken together, our findings link epigenetic alterations to metabolic dysregulation in ALS pathology, and highlight ACY-738 as a potential therapeutic strategy to treat this devastating disease."

Journal • Preclinical • Amyotrophic Lateral Sclerosis • CNS Disorders • Complement-mediated Rare Disorders • Oncology

Silencing of HDAC6 as a therapeutic target in chronic lymphocytic leukemia. (PubMed, Blood Adv) - "Furthermore, coadministration of ACY738 and ibrutinib displayed synergistic cell kill against CLL cell lines and improved overall survival compared with either single agent in vivo. These results demonstrate for the first time the therapeutic efficacy of selective HDAC6 inhibition in preclinical CLL models and suggest a rationale for the clinical development of HDAC6 inhibitors for CLL treatment, either alone or in combination with Bruton tyrosine kinase inhibition."

Journal

Cytoarchitectural changes induced by chronic cephalic pain are reversed by HDAC6 inhibition (Neuroscience 2019) - "Pretreatment with ACY738 not only resulted in decreased CSD events, but also reversed cytoarchitectural alterations. Together our results demonstrate that migraine pathophysiology is associated with disrupted neuronal cytoarchitecture and that HDAC6 inhibitors could be a novel therapeutic target for this disorder."

The Selective HDAC6 Inhibitor ACY-738 Impacts Memory and Disease Regulation in an Animal Model of Multiple Sclerosis. (PubMed, Front Neurol) - "Because ACY-738 increases short-term memory only with lower amounts of EAE-inducing reagents, we hypothesize that the inflammatory-demyelinating environment induced by higher amount of EAE-inducing reagents overpowers (at day 10 post-immunization) the synaptic molecules targeted by ACY-738. These studies pave the way for developing ACY-738-like compounds for MS patients and for using ACY-738 as a probe to elucidate disease-sensitive changes at the synapses occurring early in the disease course."

Journal • Preclinical

Rna-sequencing to Dissect the Role of Selective HDAC6 Inhibition on B Cell Signaling and Germinal Formation in Lupus Nephritis (LUPUS 2019) - "...Methods : We treated 20-week-old NZB/W lupus mice with the selective HDAC6 inhibitor ACY-738 for four weeks beginning at 20 weeks-of age; at early disease...When gene signature was compared to human lupus patients, the HDAC6 inhibitor treated mice showed several inflammatory pathways were decreased. Conclusions : Taken together, these studies suggest that HDAC6 inhibition decreased B cell activation signaling pathways and reduced PC differentiation in LN, suggesting that HDAC6 inhibition may represent an effective target to treat SLE."