RGFP966 / BioMarin - LARVOL DELTA

Evaluation of the Lethal Activity and Its Mechanism of Tasquinimod in Advanced Myeloproliferative Neoplasm (MPN) in Blastic Phase (ASH 2024) - "Importantly, cotreatment with TQ (5 to 30 µM) and ruxolitinib (250 to 1000 nM), BET inhibitor OTX015 (50 to 250 nM) or pelabresib (CPI-0610) (100 to 500 nM), or BCL2/Bcl-xL inhibitor navitoclax, induced synergistic lethality in advanced MPN-BP cells, represented by delta synergy scores of >1.0 (by the ZIP method)...Co-treatment with TQ and RGFP966 (HDAC3i) induced synergistic lethality in post-MPN sAML cells...These findings demonstrate the pre-clinical efficacy of TQ and/or JAKi or BETi or with novel agents identified here in advanced MPN and MPN-AML cells. They also create the rationale to further interrogate the pre-clinical efficacy of the TQ-based combinations against cellular models of advanced MPN."

IO biomarker • Metastases • Fibrosis • Hematological Malignancies • Immunology • Leukemia • Myelofibrosis • Myeloproliferative Neoplasm • Oncology • BCL2 • BCL2L1 • CALR • CCL2 • CCND1 • CD123 • CD33 • CD34 • CD99 • CDK6 • CDKN1A • CLEC12A • CXCL12 • CXCL8 • CXCR4 • HDAC3 • IL1A • IL3RA • IL6 • ITGAM • JAK2 • MPO • MYC • NLRP3 • NSD2 • S100A8 • S100A9 • TERT • TLR4 • TNFA • TP53

HK2 drives synaptic dysfunction in fragile X syndrome via epigenetic regulation of H3K18 lactylation. (PubMed, Front Pharmacol) - "Finally, pharmacological experiments using the HDAC3 inhibitor RGFP966 were performed to examine whether modulation of H3K18la levels contributes to HK2-associated phenotypes...Taken together, these findings support a role for the HK2-H3K18la axis in synaptic dysfunction in FXS. Targeting this metabolic-epigenetic axis may provide a potential avenue for future therapeutic exploration in FXS and related neurodevelopment disorders."

Journal • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Developmental Disorders • Fragile X Syndrome • Genetic Disorders • Psychiatry • HDAC3 • HK2

Targeting microglia-mediated neuroinflammation via pH-responsive lipid nanoparticle delivery of HDAC inhibitor RGFP966 in ischemic stroke. (PubMed, Sci Technol Adv Mater) - "It efficiently crossed the BBB, accumulated in ischemic brain tissue, promoted microglial M2 polarization, attenuated neuroinflammation, reduced infarct volume, and improved neurological function in tMCAO mice. This study provides a novel targeted nanocarrier strategy for the anti-inflammatory treatment of IS."

Journal • Cardiovascular • Inflammation • Ischemic stroke • HDAC3

Study of the mechanism by which HDAC3 regulates lipid synthesis in retinal ganglion cells by modulating SREBP-1c acetylation. (PubMed, Tissue Cell) - "High glucose induces HDAC3-dependent reduction of SREBP-1c acetylation, which promotes SREBP-1c nuclear accumulation and activation of lipogenic gene transcription in retinal neuronal cells. The pathway targeted here is shown to reduce lipid toxicity and inflammatory responses, which suggests that HDAC3 inhibition may represent a potential therapeutic strategy for neurodegenerative processes in DR."

Journal • CNS Disorders • Diabetes • Diabetic Retinopathy • Dyslipidemia • Inflammation • Metabolic Disorders • Retinal Disorders • ACACA • FASN • HDAC3

RGFP966 inhibits activation of AIM2 inflammasomes to promote mitophagy to relieve acute gouty arthritis. (PubMed, PLoS One) - "MSU-induced AGA rats were treated with RGFP966 or colchicine, and physiological and pathological indicators were determined. Furthermore, RGFP966 decreased the level of reactive oxygen species (ROS), increased the level of ATP and MMP, and promoted the levels of Pink1, Parkin and LC3-II. Collectively, RGFP966 significantly alleviated AGA, and the underlying mechanism is related to promote mitophagy by inhibiting the activation of the AIM2 inflammasomes."

Journal • Immunology • Inflammation • Inflammatory Arthritis • Pain • Rheumatology • CASP1 • HDAC3 • IL18 • IL1B • IL6 • PINK1 • TNFA

HDAC3/HK2 axis in retinal endothelial cells as a driver of neovascularization. (ARVO 2026) - "In vivo studies were performed in wild-type (WT) mouse pups with the oxygen-induced retinopathy (OIR) model and treating with the HDAC3 inhibitor RGFP966 (10 mg/kg, intraperitoneal) at postnatal days 12 and 14...Conclusions We have begun to elucidate the mechanism by which HDAC3 increases HK2 expression by implicating HIF-1α as a potential mediator. We also report that HDAC3 inhibition effectively reduces neovascularization in OIR and, therefore, is a potential treatment target for ischemic retinopathies."

Age-related Macular Degeneration • Diabetic Retinopathy • Ophthalmology • Retinal Disorders • Retinopathy of Prematurity • HDAC3 • HIF1A • HK2

Role of HDAC3 in ocular angiogenesis and fibrosis (ARVO 2026) - "In vivo, RGFP966 treatment and EC-specific HDAC3 deletion both suppressed retinal vessel sprouting and reduced vascular density during postnatal development, establishing HDAC3 as essential for physiological angiogenesis. Conclusions Our results suggest a critical role for HDAC3 in angiogenesis and fibrosis, and HDAC3 inhibition could have therapeutic implications in wet AMD and other angio-fibrotic diseases."

Age-related Macular Degeneration • Macular Degeneration • Ophthalmology • Retinal Disorders • Wet Age-related Macular Degeneration • HDAC3 • TGFB1

Inhibition of HDAC3 Expression Alleviates High-Glucose-Induced Photoreceptor Cell Apoptosis and Oxidative Stress. (PubMed, J Diabetes Res) - "Our results suggest that HDAC3 is associated with apoptosis and oxidative stress of DR photoreceptors, and the inhibition of HDAC3 can reduce apoptosis and oxidative stress of DR photoreceptors. It is suggested that epigenetic therapy of HDAC3 inhibitors may have therapeutic value in the prevention and treatment of DR."

Journal • Diabetes • Diabetic Retinopathy • Gene Therapies • Inflammation • Metabolic Disorders • Ocular Inflammation • Ophthalmology • Retinal Disorders • HDAC3

Effect of RGFP966 application in key steps of sheep somatic cell nuclear transfer on cloned embryo development. (PubMed, Anim Reprod Sci) - "In conclusion, RGFP966 combined treatment optimizes early development of sheep cloned embryos by promoting oocyte maturation, improving reprogramming, and enhancing trophectoderm function, but RGFP966-induced morula apoptosis limits blastocyst rate improvement. This study provides a theoretical basis for optimizing SCNT via targeted HDAC3 regulation."

Journal • CDX2 • HDAC3

Epigenetic Suppression of RASAL1 by HDAC3 and Cofactor YY1 Promotes Fibroblast-Myofibroblast Transition and Renal Fibrosis. (PubMed, Research (Wash D C)) - "Consistently, pharmacological inhibition of HDAC3 with RGFP966 similarly restored RASAL1 expression, inhibited FMT, and alleviated renal fibrotic pathology...Notably, targeted silencing of RASAL1 abrogated the antifibrotic effects of HDAC3 inhibition both in vitro and in vivo, underscoring the functional significance of the HDAC3-YY1-RASAL1 axis in FMT and fibrogenesis. Given that FMT is a conserved feature of fibrotic diseases across multiple organs, restoring RASAL1 expression via HDAC3 and YY1 modulation offers promising therapeutic strategies for CKD and potentially broader fibrotic disorders."

Journal • Chronic Kidney Disease • Fibrosis • Immunology • Nephrology • Renal Disease • HDAC3 • YY1

HDAC3 Mediates Hippocampal Microglial Pyroptosis Via the STING/NLRP3 Pathway and Contributes To Cognitive Impairment in Sepsis-Associated Encephalopathy. (PubMed, Inflammation) - "Conversely, RGFP966 treatment effectively attenuates these abnormalities by suppressing HDAC3 expression and downstream inflammatory pathways. These findings highlight the therapeutic potential of targeting microglial HDAC3 to mitigate neuroinflammation and cognitive dysfunction in SAE, offering a novel direction for future clinical applications."

Journal • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Infectious Disease • Inflammation • Septic Shock • CX3CR1 • HDAC3 • NLRP3 • STING

HDAC3 inhibition harnesses learning-induced neurobiological mechanisms to enhance signal-in-noise responsivity in auditory cortex and behavior. (PubMed, bioRxiv) - "Difficulty hearing in noise is a widespread challenge, yet the cortical mechanisms that preserve meaningful sounds under noisy listening conditions remain unclear. We show that HDAC3 inhibition accelerates auditory learning and strengthens cortical encoding of a learned tone while suppressing background noise activity in ways that predict improved behavioral detection. These findings reveal an experience-driven cortical mechanism that supports improved hearing in challenging listening environments, which may inform strategies for enhancing auditory learning and rehabilitation using HDAC3 drug-targets."

Journal • HDAC3

P300/CBP acetyltransferase inhibition and degradation disrupt oncogenic transcriptional programs and reveal epigenetic vulnerabilities in multiple myeloma (ASH 2025) - "Inobrodib (CCS1477), a selective P300/CBP bromodomaininhibitor, has shown promising early clinical activity in relapsed/refractory MM, highlighting thetherapeutic relevance of this axis. However, the effects of more direct P300/CBP targeting—via catalyticinhibition or protein degradation—on chromatin structure and MM lineage survival programs remainincompletely defined.Aims:We aimed to characterize the transcriptional and epigenetic effects of catalytic inhibition and targeteddegradation of P300/CBP in MM, identify determinants of resistance and sensitivity, and explore rationalepigenetic drug combinations.MM cell lines were treated with selective small-molecule P300/CBP catalytic inhibitors (A-485, A-241), thebromodomain inhibitor GNE-781, the P300/CBP degrader dCBP-1, the HDAC3 inhibitor RGFP966, and theKDM6 demethylase inhibitor GSK-J4...Collectively, these findings establish P300/CBP as a critical epigenetic dependency in MM, essential formaintaining enhancer..."

IO biomarker • Hematological Malignancies • Multiple Myeloma • Targeted Protein Degradation • HDAC3 • IRF4 • KDM6A • NCOR1 • SLAMF7 • TNFRSF17

Mechanism of butyrate remodeled calcium signaling in NK cells reverses daratumumab resistance in multiple myeloma (ASH 2025) - "MethodsWe conducted integrated multi-omics analysis on 40 subjects (10 newly diagnosed MM, 10 Dara-sensitive,10 Dara-resistant , including 16S rRNA sequencing, serum metabolomics, and single-cell RNA sequencing.In vitro functional assays utilized NK-MM co-culture systems with butyrate supplementation, Orai1inhibitor (MRS1845), and HDAC3 modulators (inhibitor RGFP966/activator ITSA). Butyratedeficiency disrupts NK cell cytotoxicity via suppressed Orai1-mediated calcium signaling, which is rescuedby butyrate through HDAC3 inhibition and subsequent epigenetic activation of Orai1. Targeting thisaxis via butyrate prodrugs, probiotics, or selective HDAC3 inhibitors represents a promising translationalstrategy to overcome Dara resistance in MM."

IO biomarker • Hematological Malignancies • Multiple Myeloma • HDAC3 • IFNG • RAI1

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

Metabolomics identifies riboflavin as a therapeutic agent for acute pancreatitis. (PubMed, J Nutr Biochem) - "Rescue experiments using the HDAC3 inhibitor RGFP966 further provided pharmacological evidence for a mechanistic link between the acetate-HDAC3 axis and riboflavin's protective effects. Collectively, these findings reveal that riboflavin alleviates AP, and its effect is associated with the modulation of the acetate-HDAC3 axis, offering a novel therapeutic strategy for this condition."

Journal • Inflammation • Metabolic Disorders • Pancreatitis • HDAC3

Molecular modeling to simulation: insights into Gaussian QSAR, molecular docking, and DFT for identification of HDAC3 inhibitors for neurocognitive vascular dementia. (PubMed, Sci Rep) - No abstract available

Journal • Alzheimer's Disease • CNS Disorders • Dementia • HDAC3

Efficacy of Combinations of Targeted Agents Against Dependencies in Mecom Rearranged AML Identified By Unbiased Chemical and CRISPR Screens (ASH 2024) - "Treatment of 3q26.2-r AML cell lines for 96-hours with ORY001 (LSD1i; 3-100 nM), RGFP966 (HDAC3i; 0.5-10 µM) or GNE-781 (CBP/p300i; 10-1000 nM) induced moderate, dose-dependent cell death, as determined by flow cytometry...Treatment of the luciferized 3q26.2-r PD AML242 model, engrafted in NSG mice, with mivebresib (0.5 mg/kg, daily 5x per week), dactolisib (20 mg/kg, daily 5x per week) or LCL161 (65 mg/kg, daily 5x per week) reduced AML burden and increased survival compared to vehicle-treated mice (p < 0.05)...These treatments resulted in reduction of EVI1 and c-Myc levels, associated with preclinical differentiation and apoptotic activity in the 3q26.2-r AML cell models. Further in vivo evaluation of the efficacy of BETi or LSD1i-based combinations against 3q26.2-r AML is warranted."

Clinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • BRD4 • CD86 • GATA2 • HDAC3 • ITGAM • MECOM • MYC • PIK3CA • XIAP

HDAC3 Is Required for Pathognomonic Features of Langerhans Cell Histiocytes (ASH 2023) - "Treating LCH-like cells with RGFP966, an HDAC3-specific inhibitor, increased apoptosis indicated by annexin-V and DAPI staining, reduced expression of Bcl-2, increased CCR7 expression, and decreased S6 phosphorylation (an indication of decreased mTOR activity), showing that pharmacological inhibition of HDAC3 may prove therapeutically efficacious by abrogating pathognomonic features of LCH cells...We further show, HDAC3 is required for multiple pathognomonic features of LCH cells and could be a promising drug target. Furthermore, if HDAC3 is required for the development of pathological DC and DC progenitors, HDAC3 blockade would address a great need in treatment of patients with LCH."

IO biomarker • Hematological Malignancies • Langerhans Cell Histiocytosis • Oncology • Pediatrics • ANXA5 • BCL2 • CCR7 • CSF1R • HDAC3 • ITGAX • RUNX3 • SPI1

CRISPR Screen Identifies HDAC3 as a Novel Radiosensitizing Target in Small Cell Lung Cancer. (PubMed, Mol Cancer Ther) - "This repair defect sensitized cells to PARP inhibitors, for which combining RGFP966 with olaparib or talazoparib produced additive to synergistic effects. Collectively, we identified HDAC3 as a novel radiosensitizing target in SCLC. Its functional loss increased the generation and persistence of IR-induced DNA DSBs, effectively sensitizing SCLC cell lines and xenografts to IR, providing a potential radiosensitization strategy to treat SCLC."

Journal • Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor • HDAC3

HDAC3 mediates retinal endothelial cell metabolic reprogramming and angiogenesis. (PubMed, Acta Pharmacol Sin) - "Cells were treated with the HDAC3 inhibitor, RGFP966, the mitochondrial fission inhibitor, Mdivi-1 or DMSO as a control...In a similar fashion, the inhibition of mitochondrial fission with Mdivi-1 mitigates the glycolytic shift and HK2 expression. These findings suggest a working model in which HDAC3-induced mitochondrial fission upregulates HK2, induces glycolysis and promotes REC pathological angiogenesis."

Journal • Age-related Macular Degeneration • Diabetic Retinopathy • Ophthalmology • Retinal Disorders • Retinopathy of Prematurity • HDAC3 • HK2

CRISPR Screen Identifies HDAC3 as a Novel Radiosensitizing Target in Small Cell Lung Cancer. (PubMed, Mol Cancer Ther) - "This repair defect sensitized cells to PARP inhibitors, where combining RGFP966 with Olaparib or Talazoparib produced additive to synergistic effects. Collectively, we identified HDAC3 as a novel radiosensitizing target in SCLC. Its functional loss increased the generation and persistence of IR-induced DNA DSBs, effectively sensitizing SCLC cell lines and xenografts to IR, providing a potential radiosensitization strategy to treat SCLC."

Journal • Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor • HDAC3

HDAC3 represses Nrf2-GDF11 signaling to drive chondrocyte adipogenesis in temporomandibular joint osteoarthritis. (PubMed, J Adv Res) - "Our findings indicate that aberrant biomechanical force induces HDAC3 upregulation, which suppresses Nrf2-mediated transactivation of GDF11, thereby promoting chondrocyte adipogenesis and exacerbating TMJ OA progression."

Journal • Immunology • Osteoarthritis • Pain • Rheumatology • ACAN • GDF11 • HDAC3 • NFE2L2

Inhibition of HDAC3 induces neuroprotection by activating the Npas4 signaling pathway following surgical brain injury in rats. (PubMed, Iran J Basic Med Sci) - "The effects of RGFP966, a specific HDAC3 inhibitor, were assessed by western blotting, immunofluorescence, neurological scoring, and fluoro-Jade C staining...HDAC3 plays a role in rats' complex pathogenesis of SBI. HDAC3 inhibition imparts a protective role in early brain injury in SBI in rats by regulating autophagy and inflammation via up-regulation of Npas4."

Journal • Preclinical • CNS Disorders • Inflammation • Vascular Neurology • HDAC3

Targeting HDAC3 Suppresses Ferroptosis and Demyelination in White Matter Injury by Restoring PDK4-Mediated Iron Homeostasis. (PubMed, CNS Neurosci Ther) - "HDAC3 drives ferroptosis in WMI via iron metabolism and lipid peroxidation, highlighting the HDAC3-PDK4 axis as a therapeutic target."

Journal • CNS Disorders • Hematological Disorders • Solid Tumor • HDAC3 • PDK4