CRA-026440 / Quest Diagnostics - LARVOL DELTA

" Improving the beneficial effects of HDAC8 inhibition by simultaneously activation of SIRT1 in a zebrafish model of Duchenne muscular dystrophy". (PubMed, Pharmacol Res) - "In this study, we investigated the therapeutic efficacy of combining selective HDAC8 inhibition (PCI-34051) with SIRT1 activation (SRT2104) in a zebrafish model of DMD. Overall, these findings demonstrate that combined HDAC8 inhibition and SIRT1 activation effectively ameliorate key pathological features of DMD in zebrafish and provide mechanistic insights into the complementary pathways targeted by the two compounds. This work supports the development of combinatorial epigenetic strategies as potential therapeutic approaches for DMD."

Journal • Duchenne Muscular Dystrophy • Fibrosis • Genetic Disorders • Immunology • Inflammation • Metabolic Disorders • Muscular Dystrophy • HDAC8 • SIRT1

Development of Indole-3-yl-methylene-thiobarbital Derivatives as Inhibitors of HDAC8 Enzyme Activity. (PubMed, J Med Chem) - "Although hydroxamic acid-based inhibitors, like PCI-34051, have demonstrated potent HDAC8 inhibition, limitations including poor selectivity, instability, and off-target effects underscore the need for novel scaffolds...Furthermore, compound 3r selectively induced SMC3 hyperacetylation in THP-1 cells, confirming its functional HDAC8 inhibition. Computational modeling and molecular dynamics simulations rationalized the experimental SAR and suggested an allosteric mechanism of inhibition."

Journal • Oncology • HDAC1 • HDAC8

HDAC8-selective inhibitor PCI-34051 protects against aortic dissection by attenuating ferroptosis of vascular smooth muscle cells. (PubMed, Life Med) - "More importantly, PCI-34051 reduced BAPN-induced AD incidence and aortic rupture mortality in mice by inhibiting HASMC ferroptosis and inflammatory response. Taken together, inhibition of HDAC8 by PCI-34051 may provide a preventive or therapeutic strategy for AD by attenuating HASMC ferroptosis."

Journal • Cardiovascular • Congestive Heart Failure • Fibrosis • Heart Failure • Immunology • Inflammation • FOS • HDAC8 • JUN

HDAC8 impairs tight junctions in allergic rhinitis through Smad7 deacetylation. (PubMed, Front Immunol) - "In vivo, PCI-34051 treatment improved nasal epithelial integrity and modulated Th1/Th2/Th17/Treg-associated cytokine profiles. These findings support that HDAC8-mediated reduction of Smad7 acetylation contributes to epithelial barrier dysfunction in AR, highlighting HDAC8 as a potential therapeutic target for restoring mucosal homeostasis."

Journal • Allergic Rhinitis • Immunology • Inflammation • CLDN1 • HDAC8 • OCLN • SMAD7 • TJP1

Discovery of 6-substituted indole and tetrahydroquinoline derivatives as selective HDAC8 inhibitors. (PubMed, Bioorg Med Chem) - "Through systematic structural modification of the known inhibitor PCI-34051, we designed and synthesized two novel series of compounds: 6-substituted indoles and 6-substituted tetrahydroquinolines...Preliminary data indicated that compound 11k could modulate cytokine expression in T-cells, highlighting a potential non-cytotoxic biological effect that warrants further investigation. This work introduces novel chemotypes, notably the tetrahydroquinoline scaffold, for the development of selective HDAC8 inhibitors."

Journal • Oncology • HDAC8

Discovery of Histone Deacetylase 8-Specific Proteolysis-Targeting Chimeras with Anticancer Activity against Hematological Malignancies. (PubMed, J Med Chem) - "The pomalidomide/thalidomide-based series (BP1-BP5) exhibited strong antiproliferative activity against leukemia and multiple myeloma cells, accompanied by degradation of CRBN neosubstrates. The hit compounds from both series, BP1 (DC50, 24 h = 20 nM, Dmax, 24 h = 99%) and BP6 (DC50, 24 h = 81 nM, Dmax, 24 h = 93%), demonstrated highly efficient and selective HDAC8 degradation. Pretreatment with BP6 enhanced the tumor suppressor p53 stability, thereby significantly increasing the sensitivity of leukemia cells to the MDM2 antagonist idasanutlin than PCI-34051, highlighting its unique potential for combinatorial therapy without impacting neosubstrates."

Journal • Hematological Disorders • Hematological Malignancies • Leukemia • Multiple Myeloma • Oncology • Targeted Protein Degradation • CRBN • HDAC8 • TP53

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

Immunogenic cell death-related genes as prognostic biomarkers and therapeutic insights in uterine corpus endometrial carcinoma: an integrative bioinformatics analysis. (PubMed, Front Oncol) - "Finally, we found that hyper-immunogenicity may be sensitive to immunotherapy and certain drugs (AZD5991, Ibrutinib, Osimertinib, AGI-5198, Savolitinib, Sapitinib, AZ960, AZD3759 and Ruxolitinib), while PCI-34051 and Vorinostat showed sensitivity in patients with hypo-immunogenicity. Our results demonstrate that ICD plays an important role in UCEC progression, suggesting that ICD-related markers could serve as potential targets for prognosis and treatment."

Biomarker • IO biomarker • Journal • Tumor mutational burden • Endometrial Cancer • Oncology • Solid Tumor • Uterine Cancer • CD52 • STAT1 • TMB

Sevoflurane-Induced Cognitive Dysfunction in Aged Mice Mediated by HDAC8-Dependent Suppression of Adult Hippocampal Neurogenesis via the pCREB/BDNF Pathway. (PubMed, Brain Res Bull) - "Notably, HDAC8 inhibition with PCI-34051 or direct BDNF administration reversed these effects, while HDAC8 overexpression recapitulated the deficits. These findings suggest that HDAC8 upregulation is a key mediator of sevoflurane-induced cognitive decline via AHN suppression, highlighting a promising therapeutic target for anesthesia-related neurotoxicity."

Journal • Preclinical • Anesthesia • Cognitive Disorders • BDNF • HDAC8

Synergistic HDAC4/8 Inhibition Sensitizes Osteosarcoma to Doxorubicin via pAKT/RUNX2 Pathway Modulation. (PubMed, Int J Mol Sci) - "In this context, the present study aimed to evaluate the therapeutic potential of combining doxo with the selective HDAC inhibitors, tasquinimod (Tas, targeting HDAC4) and PCI-34051 (PCI, targeting HDAC8), in SJSA-1 osteosarcoma cells. These findings suggest that dual HDAC inhibition with Tas and PCI can potentiate doxo efficacy by enhancing apoptosis, inhibiting proliferation, and reducing metastatic potential, thus offering a promising strategy to overcome chemoresistance in osteosarcoma. Further preclinical and clinical studies are required to validate these therapeutic benefits."

Journal • Oncology • Osteosarcoma • Sarcoma • Solid Tumor • CASP3 • CASP8 • HDAC4 • HDAC8 • MMP13 • MMP9 • RUNX2

Binding mechanism and distant regulation of histone deacetylase 8 by PCI-34051. (PubMed, Commun Biol) - "Overall, these results show the structural and dynamic regulations of hHDAC8 by PCI-34051, which induces a lower energy state for the protein-ligand system compared to SAHA, thus showing better inhibitory effects. In addition, it also suggests that certain regions, specifically loops L2 and L3, within the hHDAC8 protein could be key regions for targeted intervention."

Journal • Oncology • HDAC8

Selective HDAC8 inhibition by PCI-34051 attenuates inflammation and airway remodeling in asthma via miR-381-3p-TGFβ3 axis. (PubMed, J Transl Int Med) - "Inhibition of TGF-β3 further reduced the activation of ERK, PI3K, AKT, and PDK1. In a mouse model, HDAC8 inhibitor PCI-34051 exhibits comprehensive control of asthmatic changes, including inflammation and airway remodeling."

Journal • Asthma • Immunology • Inflammation • Pulmonary Disease • Respiratory Diseases • ENG • GAPDH • HDAC8 • MIR381 • TGFB1

Lysine deacetylase inhibitors have low selectivity in cells and exhibit predominantly off-target effects. (PubMed, FEBS Open Bio) - "We compared the effects of treatment with two of the reportedly most KDAC-selective inhibitors, Tubastatin A and PCI-34051, in HT1080 cells in which the endogenous KDAC6 or KDAC8 gene has been mutated to inactivate enzyme catalysis while retaining enzyme expression...We conclude that the majority of observed biological effects of treatment with KDAC inhibitors are due to off-target effects rather than the intended KDAC inhibition. Developing a truly specific KDAC6 inhibitor could be a promising therapeutic avenue, but it is imperative to develop new inhibitors that selectively mimic genetic inactivation of individual KDACs."

Journal • Oncology

Inhibition of HDAC8 mitigates AKI by reducing DNA damage and promoting homologous recombination repair. (PubMed, J Cell Mol Med) - "In a murine model of AKI induced by cisplatin, the administration of PCI-34051, a selective inhibitor of HDAC8, resulted in significant improvement in renal function and reduction in renal tubular damage and apoptosis. Similarly, pharmacological and genetic inhibition of HDAC8 reduced γ-H2AX and enhanced MRE11 expression; conversely, HDAC8 overexpression exacerbated these changes in mRTECs exposed to cisplatin. These results support that HDAC8 inhibition attenuates cisplatin-induced AKI through a mechanism associated with reducing DNA damage and promoting its repair."

IO biomarker • Journal • Acute Kidney Injury • Nephrology • Oncology • Renal Disease • BAX • BCL2 • CASP3 • CDK2 • CDKN1A • HDAC8 • HRD • MRE11A • TP53

Natural Derivatives of Selective HDAC8 Inhibitors with Potent in Vivo Antitumor Efficacy against Breast Cancer. (PubMed, J Med Chem) - "Upon additional modifications of corallorazine D, a candidate compound 5k, demonstrated remarkable inhibitory potency against HDAC8 (IC50 = 0.12 ± 0.01 nM), 89-fold superior to PCI-34051...Treatment with 5k significantly increased the proportion of M1 macrophages and decreased the proportion of M2 macrophages (M1/M2 ratio = 2.67 ± 0.25). 5k represents a promising compound for further investigation as a potential treatment for breast cancer."

Journal • Preclinical • Breast Cancer • Oncology • Solid Tumor • HDAC8

Discovery of a Highly Potent and Selective HDAC8 Degrader: Advancing the Functional Understanding and Therapeutic Potential of HDAC8. (PubMed, J Med Chem) - "YX862 exhibits promising on-target antiproliferative activity against DLBCL cells with higher potency than the HDAC8 selective inhibitor PCI-34051. As a selective HDAC8 degrader that avoids pan-HDAC inhibition, YX862 represents a valuable tool for exploring the biological and therapeutic potential of HDAC8."

Journal • Diffuse Large B Cell Lymphoma • Oncology • Targeted Protein Degradation • HDAC3 • HDAC8

Replacement of the hydroxamic acid group in the selective HDAC8 inhibitor PCI-34051. (PubMed, Bioorg Med Chem Lett) - "Evaluation of the analogs' affinity to Zn indicated that none had affinity for Zn within the same range as the HA. These studies point to the difficulty in the application of bioisosteric replacements for Zn binding motifs."

Journal • HDAC8

Inhibition of HDAC8 Reduces the Proliferation of Adult Neural Stem Cells in the Subventricular Zone. (PubMed, Int J Mol Sci) - "Treatment with the selective HDAC8 inhibitor PCI-34051 reduced the neurosphere size in cultures from the SVZ of adult mice...HDAC8 inhibition in adult SVZ neurospheres upregulated the cytokine-mediated signaling and downregulated the cell cycle pathway. In conclusion, HDAC8 participates in the regulation of in vivo proliferation and differentiation of NSCs/NPCs in the adult SVZ, which provides insights into the underlying molecular mechanisms."

Journal • HDAC8

Cell lines expressing catalytically inactive lysine deacetylase to assess inhibitor specificity | Poster Board #308 (ACS-Sp 2024) - "Comparing these cells lines to wild-type cells treated with Tubastatin A or PCI-34051, inhibitors reported as specific for KDAC6 and KDAC8 respectively, we see biologically significant differences both at the protein acetylation level and the gene expression level...These results indicate that the inhibitors, although they appear to be specific in vitro, are having off-target effects in a cellular context. We propose that these cell lines can be used to test new and existing HDAC inhibitors, to aid in the identification of more specific and thus more effective therapeutic candidates."

Preclinical • CNS Disorders • Oncology

Inhibition of PI3K-AKT-mTOR pathway and modulation of histone deacetylase enzymes reduce the growth of acute myeloid leukemia cells. (PubMed, Med Oncol) - "However, LY294002 + SAHA and LY294002 + PCI-34051 resulted in G0/G1 and G2/M cell cycle arrest in CMK cells, respectively...In addition, the expression of LC3BII was elevated in the CMK cell line. In conclusion, although more mechanistic studies are required, a combinational inhibition of PI3K and HDAC could be a promising approach for AML."

Epigenetic controller • Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

Curcumin and PCI-34051 combined treatment ameliorates inflammation and fibrosis by affecting MAP kinase pathway. (PubMed, Inflammopharmacology) - "Present study indicates protective effects of HDAC8 inhibition in asthma using HDAC8 using CUR and PCI alone or in combination, attenuates airway inflammation, fibrosis and remodeling; hence, bronchoconstriction was accompanied through modulation of MAP kinase pathway."

Journal • Asthma • Cough • Fibrosis • Immunology • Inflammation • Pulmonary Disease • Respiratory Diseases • MMP9

Sulforaphane Mitigates High-Fat Diet-Induced Obesity by Enhancing Mitochondrial Biogenesis in Skeletal Muscle via the HDAC8-PGC1α Axis. (PubMed, Mol Nutr Food Res) - "SFN prevents obesity-related metabolic dysregulation by enhancing mitochondrial biogenesis and function via targeting the HDAC8-PGCα axis. These results suggest SFN as a beneficial anti-obesity agent providing new insight into the role of HDAC8 in the PGC1α-mediated mitochondrial biogenesis, which may be a novel and promising drug target for metabolic diseases."

Journal • Genetic Disorders • Metabolic Disorders • Obesity

Endogenous expression of inactive lysine deacetylases reveals deacetylation-dependent cellular mechanisms. (PubMed, PLoS One) - "Treatment of wild-type cells with KDAC-specific inhibitors Tubastatin A and PCI-34051 resulted in gene expression changes distinct from those of the engineered cell lines, validating this approach as a tool for evaluating in-cell inhibitor specificity and identifying off-target effects of KDAC inhibitors. Probing the functions of specific KDAC domains using these cell lines is not equivalent to doing so using previously existing methods and provides novel insight into the catalytic functions of individual KDACs by investigating the molecular and cellular changes upon genetic inactivation."

Journal

A novel, effective machine learning-based RNA editing profile for predicting the prognosis of lower-grade gliomas. (PubMed, Heliyon) - "The sensitivity of PCI-34051 and Elephantin was significantly higher in the high-risk group than the low-risk group, thus potentially providing a marker to predict the effects of lung cancer drug treatment. RNA editing may serve as a novel survival prediction tool, thus offering hope for developing editing-based therapeutic strategies to combat LGG progression. In addition, this tool may help optimize survival risk assessment and individualized care for patients with low-grade gliomas."

IO biomarker • Journal • Machine learning • Brain Cancer • CNS Tumor • Glioma • Lung Cancer • Oncology • Solid Tumor • SOD2

Are inhibitors of histone deacetylase 8 (HDAC8) effective in hematological cancers especially acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL)? (PubMed, Eur J Med Chem) - "A specific HDAC8 inhibitor PCI-34051 showed promising results against both T-cell lymphoma and AML. Here, we summarize the role of HDAC8 in hematological malignancies, especially in AML and ALL. This article also introduces the structure/function of HDAC8 and a special attention has been paid to address the HDAC8 enzyme selectivity issue in hematological cancer especially against AML and ALL."

Epigenetic controller • Journal • Review • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Lymphoma • Oncology • T Cell Non-Hodgkin Lymphoma • RAI1