trichostatin A (VTR-297) / Vanda - LARVOL DELTA

Pathogenic variants at the N-terminal arginine residue 44 disrupt human GABA transporter 1 function: insights from Drosophila epilepsy models. (PubMed, Front Pharmacol) - "Proteasome inhibitors (MG-132, bortezomib) and the HDAC inhibitor trichostatin A (TSA) partially rescued R44Q function. Moreover, R44Q-expressing flies presented heat-induced seizures, which were mitigated by 4-phenylbutyrate (4-PBA) treatment. These findings elucidate the molecular basis of R44-mediated hGAT-1 dysfunction and highlight potential therapeutic avenues for SLC6A1-related neurodevelopmental disorders."

Journal • CNS Disorders • Developmental Disorders • Epilepsy • Psychiatry

TMOD2 and DOCK4 as Novel Gut Microbiota-Associated Biomarkers for Colorectal Adenoma: Integrated Transcriptomic Analysis and Therapeutic Target Identification. (PubMed, Mediators Inflamm) - "Drug screening identified 22 potential therapeutic compounds, with trichostatin A showing optimal binding affinity. These findings establish TMOD2 and DOCK4 as novel biomarkers linking GM dysbiosis to CRA development, opening new avenues for microbiome-targeted early intervention strategies."

Biomarker • Journal • Colorectal Cancer • Oncology • Solid Tumor • EIF6

Therapeutic Perspectives of SIRT6 Regulation: Computational Analysis of Activation and Inhibition by Bioactive Molecules. (PubMed, J Mol Recognit) - "Therefore, we investigated the interactions between the ligands quercetin (QUE), isoquercetin (ISO), catechin gallate (CG), and trichostatin A (TSA) with SIRT6, using computational methods from the perspective of molecular modeling through the Molecular Fractionation with Caps Conjugates (MFCC) technique and according to the calculation parameters of Density Functional Theory (DFT)...In addition, residues such as PRO62, MET136, MET157, and VAL115 stand out as key components of the protein active site. These findings offer strategic insights into the molecular mechanisms underlying the binding of the studied ligands to SIRT6, providing a deep understanding of their affinity and pharmacological potential."

Journal • Metabolic Disorders • Oncology • SIRT6

The impact of histone deacetylase inhibition on neurobehavioural outcomes in preclinical models of traumatic and non-traumatic spinal cord injury: a systematic review. (PubMed, Front Immunol) - "Valproate was the most frequently studied HDAC inhibitor (n=20), followed by 4-phenylbutyrate (4-PBA; n=7) and RGFP966 (n=3). Trichostatin A, tubastatin A, entinostat, PCI-34051, scriptaid, CI-994, TMP269, vorinostat, 3-TYP, SW-100 and ACY1215 were each evaluated in a single study. Three studies used the sirtuin-1 (HDAC class III) inhibitor EX527 administered with an activator molecule: melatonin (n=1), MLN4924 (n=1) and oxymatrine (n=1)...These results support further investigation of HDAC inhibitors in preclinical studies before translation into clinical trials. https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42023477882."

Journal • Preclinical • Review • CNS Disorders • Orthopedics • Pain • Psychiatry • Reperfusion Injury • SIRT1

Selective HDAC4 inhibition by SP1-PTD promotes odontoblast differentiation. (PubMed, J Appl Oral Sci) - "SP1-PTD represents a first-in-class selective HDAC4 inhibitor that achieves robust pro-differentiation effects with an exceptional safety profile. By specifically targeting HDAC4-SMRT interactions, SP1-PTD overcomes limitations of conventional HDAC inhibitors and offers translational promise for dental regenerative medicine."

Journal • BGLAP • DSPP • HDAC4 • RUNX2

Trichostatin A Sensitizes Tumor Cells to Apoptosis Induced by Soluble Trimeric TRAIL-Expressing Human Mesenchymal Stromal Cells. (PubMed, Cancer Sci) - "These in vivo findings indicate that efficient tumor targeting by MSCs is crucial for achieving therapeutic efficacy, especially in TRAIL-resistant tumors. Overall, our results demonstrate that co-treatment with TSA enhances the antitumor effect of TRAIL-expressing MSCs, offering a potential strategy to overcome TRAIL resistance and improve MSC-based cancer therapies."

Journal • Oncology • CASP8

Comparative Study of Histone Deacetylase Inhibitors for Radiation Protection Using Survival Outcomes in a Mouse Model. (PubMed, Biol Pharm Bull) - "Male ICR mice received 7.5 Gy TBI followed by a single administration of valproic acid (VPA; 300 or 600 mg/kg), sodium butyrate (NaB; 500 or 1000 mg/kg), trichostatin A (TSA; 0.5 or 1.0 mg/kg), vorinostat (10 or 50 mg/kg), panobinostat (25 or 50 mg/kg), givinostat (5 or 10 mg/kg), or entinostat (25 or 50 mg/kg). VPA's efficacy may reflect a combination of effects on DNA repair, inflammation, and redox regulation rather than HDAC inhibition alone. These findings suggest VPA to be a promising candidate for radioprotection and emphasize the need for further studies to optimize dosing and explore underlying mechanisms."

Clinical • Journal • Preclinical • Inflammation

Epigenetically inhibiting CYP3A5 modulates the migration and invasion of esophageal squamous cell carcinoma. (PubMed, Drug Metab Dispos) - "Intriguingly, administration of the histone deacetylase inhibitor trichostatin A resulted in the upregulation of CYP3A5 expression...Because ESCC develops, CYP3A5 suppression promotes tumor metastasis and invasion. CYP3A5 is a potential biomarker and therapeutic target for ESCC."

Journal • Esophageal Cancer • Esophageal Squamous Cell Carcinoma • Oncology • Squamous Cell Carcinoma • CREBBP • CYP3A5 • HDAC4

Microhand Platform Equipped with Plate-Shaped End-Effectors Enables Precise Probing of Intracellular Structure Contribution to Whole-Cell Mechanical Properties. (PubMed, Micromachines (Basel)) - "To validate the system's sensitivity, we precisely quantified the mechanical contributions of subcellular components, such as the actin cytoskeleton and chromatin, by measuring stiffness reductions after treatment with Cytochalasin D and Trichostatin A, respectively...Furthermore, by controlling the indentation speed and depth, the mechanical properties of the cytoplasm and nucleus could be distinctly evaluated. These results demonstrate that our microhand system is a highly sensitive and robust platform, capable of detecting subtle, disease-related changes and elucidating the contributions of specific subcellular structures to cell mechanics."

Journal

Chronic alcohol intake elicits distinct multi-omic profiles in the liver versus skeletal muscle of mice. (PubMed, bioRxiv) - "Finally, computational drug repurposing identified several compounds for therapeutic targeting of alcohol-induced liver (e.g., saracatinib, GSK126) and muscle (e.g., metformin, trichostatin A) pathophysiology, perhaps working partly to counter metabolic dysregulation. Overall, our study provides a tractable list of therapeutic targets and treatments to help expedite the understanding of and countermeasures against alcohol-related liver disease and alcohol-related myopathy in humans."

Journal • Preclinical • Hepatology • Metabolic Disorders • Myositis

MONOPTEROS isoform MP11ir plays a role during somatic embryogenesis in Arabidopsis thaliana. (PubMed, Plant Physiol) - "High levels of MP11ir transcript are observed during auxin- and trichostatin A-dependent induction of somatic embryogenesis...Our results suggest that these auxin-related genes might be targets of MP11ir and/or MP. Consequently, any adjustment to MP activity alters auxin homeostasis and endogenous auxin levels, hindering embryogenic transition."

Journal

Truncated APC impairs innate immune response by targeting MAVS on mitochondria in colorectal cancer. (PubMed, J Transl Med) - "Our study reveals a previously unrecognized role of Trunc-APC in dampening tumor-intrinsic innate immunity and suggests that co-targeting Trunc-APC with epigenetic therapy may offer a promising strategy to enhance anti-tumor immune responses in CRC."

Journal • Colorectal Cancer • Gene Therapies • Oncology • Solid Tumor • Targeted Protein Degradation • APC

Acetylation and Transcriptomic Activity of Vtr-297 - Results from an Ongoing Phase I Clinical Trial (ASH 2024) - P1 | "In an ongoing clinical study, we will further monitor, validate, and expand on these findings. Further observations at higher, safe, and clinically meaningful doses will complement our current, early activity of VTR-297 and how it can be used to optimize patient treatments."

Clinical • P1 data • Acute Myelogenous Leukemia • Hematological Malignancies • Hodgkin Lymphoma • Leukemia • Lymphoma • Multiple Myeloma • Myelodysplastic Syndrome • Non-Hodgkin’s Lymphoma • Oncology • FLT3 • NTRK3

Complementary Roles of DNMT3A and TET2 KO in Sculpting CD4-T Cells for Sustained Proliferation without Exhaustion to Promote Lymphomagenesis (ASH 2024) - "Furthermore, HDAC inhibition with Trichostatin A in DNMT3A KO cells promoted similar genes upregulated as in TET2 KO...TET2 and DNMT3A appeared to have divergent and yet often complementary roles in balancing T cell exhaustion and activation despite their opposite functions in DNA methylation. Importantly, some of the phenotypes observed with TET2 KO may be related to its normal function in histone deacetylation whose loss could lead to aberrant gene expression and the amplified expression of some genes with hypomethylation due to DNMT3A KO."

IO biomarker • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Peripheral T-cell Lymphoma • T Cell Non-Hodgkin Lymphoma • CCR4 • CCR7 • CD4 • DNMT3A • HDAC1 • ICOS • IRF4 • PLCG1 • PRDM1 • TBX21 • TET2

Design, Synthesis, and Biological Evaluation of Novel 7-Hydroxycoumarin- Based N-Hydroxyamides as Histone Deacetylase Inhibitors and Cytotoxic Agents. (PubMed, Med Chem) - "The research results suggest that some hydroxamic acids (5a and 7k) warrant further evaluation, and these results could serve as a basis for designing more potent HDAC inhibitors and antitumor agents."

Journal • Oncology

HDAC inhibitors restore osteoimmune balance and bone regeneration via selective MAPK modulation in inflammatory bone disease. (PubMed, Stem Cell Res Ther) - "TSA, PXD, and MGCD function as dual-action therapeutics by regulating macrophage polarization and enhancing osteogenesis, thereby establishing a pro-regenerative microenvironment and reversing inflammatory bone loss. These findings provide mechanistic insight into the epigenetic control of immune-bone crosstalk and support a drug-repurposing strategy that utilizes clinically available HDAC inhibitors to accelerate the development of osteoimmunomodulatory therapies."

Journal • Gene Therapies • Inflammation • Orthopedics • Osteoporosis

Histone deacetylase 6 modulates autophagy through HIF-1α/BNIP3 signaling in lung cancer. (PubMed, Biochem Pharmacol) - "Moreover, pharmacological inhibition of HDAC with Trichostatin A (TSA) suppressed both HDAC6 and BNIP3 expression, decreased autophagic activity, and reduced lung tumor formation in a KRASG12D+/P53loxP/loxP transgenic mouse model. Collectively, these results reveal a novel HDAC6-HIF-1α-BNIP3 axis that governs autophagy in lung cancer and underscore the potential of HDAC6 as a therapeutic target for modulating autophagy and inhibiting lung tumor progression."

Journal • Lung Cancer • Oncology • Solid Tumor • BNIP3 • HDAC6 • HIF1A • KRAS

Optimizing CRISPR/Cas-Mediated CD-19 CAR knock-in efficiency, cell viability and cell expansion in human primary T cells using a cGMP-compliant electroporation platform (ESGCT 2024) - "Complexing Ribonucleoproteins (RNPs) with anionic polymer PGA (Poly-L-Glutamic acid) or treating T cells post-EP with Homology-Directed Repair (HDR) enhancing small molecules such as, M3814, Trichostatin A (TSA) and a commercial HDR enhancer further increased the GFP knock-in efficiency by 3-5-fold, depending on the small molecule used. As with GFP KI, addition of PGA in RNP or HDR enhancing drug post-EP further enhanced the CD-19 CAR KI efficiency by 2-3-fold. In summary, we present data on KO/KI optimization, cell viability, cell expansion, cell phenotyping and potency assay post electroporation and clearly demonstrate that using MaxCyte’s GMP-compliant electroporation platform and GenScript’s reagents can engineer T cells from multiple donors with high efficiency that can be used for the treatment of diseases including cancer."

RAB11A

Cytotoxic, anti-inflammatory, antioxidant, and anti-glyoxalase-I evaluation of chelating substances: In silico and in vitro study. (PubMed, PLoS One) - "Further assessment of molecular action mechanisms and structural betterments/enhancements and/or derivatization of promising potent agents with antiglyoxylase - antiinflammation duality along with differential cytotoxicity and reductive capacities are advisably warranted with appropriately matched downstream in vivo validation modalities."

Journal • Preclinical • Colorectal Cancer • Oncology • Solid Tumor

Rapid Restoration of Cell Phenotype and Matrix Forming Capacity Following Transient Nuclear Softening. (PubMed, Acta Biomater) - "We recently employed transient histone deacetylase inhibition with trichostatin A (TSA) treatment to increase nuclear deformability (decrease nuclear stiffness) to overcome the stiff nuclear impediments to cell migration through dense tissues and electrospun matrices...Importantly, meniscal cells completely restored their transcriptional phenotype and maintained their capacity to respond transcriptionally and functionally to a secondary pro-matrix stimuli (i.e., transforming growth factor β3) within 7 days after cessation of TSA treatment. Together, this work defines the efficacy, reproducibility, safety, and feasibility of future translational approaches for nuclear softening to treat dense connective tissue injuries."

Journal

A male-dominant cell group expressing calbindin-D28K and androgen receptor in the mouse preoptic area requires postnatal testicular androgens and histone deacetylation. (PubMed, J Neuroendocrinol) - "Immunohistochemistry for Calb and AR was performed using the brain sections from pubertal male mice subjected to sham surgery or neonatal orchidectomy, from pubertal female mice treated with vehicle, testosterone, or estradiol during the postnatal period, and from pubertal male mice whose brains were treated with trichostatin A, a histone deacetylase inhibitor, during the postnatal period...These findings suggest that estrogens synthesized from postnatal testicular androgens act selectively on the AR-expressing subpopulation of Calb neurons, contributing to the sex difference in the number of Calb neurons in the mouse Calb-SDN. Epigenetic regulation of gene expression, possibly mediated by histone deacetylation, may be involved in the emergence of the AR-expressing subpopulation of Calb neurons."

Journal • Preclinical • AR • CALB1

Histone H4K16 acetylation modification regulated autophagy and apoptosis in neuron after spinal cord injury. (PubMed, Sci Rep) - "Pharmacological inhibition of deacetylases by Trichostatin A (TSA) restored H4K16ac, suppressed autophagy, and exacerbated apoptosis. Similarly, Sirtuin 1 (SIRT1) knockdown upregulated H4K16ac, inhibited autophagic flux, and promoted apoptosis via the Bax/Bcl-2/caspase-3 pathway. These findings reveal that H4K16ac downregulation post-SCI enhances autophagy as a protective response, while its restoration via SIRT1 inhibition disrupts this balance, aggravating neuronal apoptosis."

IO biomarker • Journal • CNS Disorders • Oncology • Orthopedics • Solid Tumor • ATG5 • BAX • BCL2 • BECN1 • CASP3

Identification of Potent HDAC6 Inhibitors for Breast Cancer Through Multi-Stage In Silico Modeling. (PubMed, Bioinform Biol Insights) - "The HDI-3 emerged as the most promising candidate among replicate simulations, exhibiting a substantially favorable MM/GBSA binding free energy of -130.67 kcal/mol-indicative of strong thermodynamic stability and stronger binding affinity compared to reference inhibitors Trichostatin A and Ricolinostat. Therefore, experimental validation is essential to confirm the compound's efficacy and safety. This integrated computational pipeline provides an efficient strategy to accelerate targeted drug discovery, laying the groundwork for future experimental investigations."

Journal • Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • ER • HDAC6

H3K9 acetylation-NF-κB-AP-1 nexus targeted by ITE limits TNF-α-induced MMP-9 expression in monocytic cells. (PubMed, J Immunol) - "Conversely, the acetylation induced by trichostatin A effectively reverses the inhibitory action of ITE. Moreover, increased TNF-α-induced binding of NF-κB or AP-1 at the MMP-9 promoter region was inhibited by ITE, resulting in suppression of MMP-9 gene expression. In conclusion, our study demonstrates that ITE reduces the TNF-α-induced MMP-9 expression via the H3K9 acetylation/NF-κB/AP-1 axis, highlighting a potential mechanism for mitigating MMP-9-related inflammatory disorders."

Journal • Inflammation • MMP9 • NFKB1 • TNFA • TNFRSF1A

An enteropathogenic microbial toxin modulates the breast cancer epigenome resulting in concurrent silencing of tumor suppressor genes. (PubMed, Breast Cancer Res) - "Collectively, BFT exposure epigenetically modifies the expression of TSGs and impacts migration/invasion potential of breast cancer cells, and treatment with demethylation agent(s) and HDAC inhibitors effectively diminishes the functional impact of BFT."

Journal • Breast Cancer • Infectious Disease • Oncology • Solid Tumor • FAT4