RGFP966 / BioMarin - LARVOL DELTA

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

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

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

Inhibition of histone deacetylases 3 attenuates imiquimod-induced psoriatic dermatitis via targeting cGAS-STING signaling in keratinocytes. (PubMed, J Transl Med) - "Our findings establish HDAC3 as a pivotal mediator of psoriasis pathogenesis through the cGAS-STING pathway via mitochondrial dysfunction. The role of HDAC3 in exacerbating epidermal hyperproliferation and inflammation highlights its potential as a therapeutic target. Targeting HDAC3 in keratinocytes may offer a novel strategy for preventing and treating psoriasis by modulating epigenetic regulation, mitochondrial homeostasis, and innate immune responses."

Journal • Dermatitis • Dermatology • Immunology • Inflammation • Metabolic Disorders • Psoriasis • HDAC3

PIM1 Phosphorylates HDAC3 for IL33 Deacetylation to Exacerbate Allergic Airway Inflammation (ATS 2025) - "Additionally, asthmatic mice were treated with the PIM1 inhibitor SGI-1776 and the HDAC3 inhibitor RGFP-966... Our findings suggest that the PIM1-HDAC3-IL-33 axis in epithelial cells plays a significant role in regulating the degree of inflammation in asthma, potentially representing a novel therapeutic mechanism for allergic asthma."

Asthma • Inflammation • Respiratory Diseases • HDAC3 • IL33 • PIM1

HDAC3 inhibition mitigates acute kidney injury by alleviating RIPK1-mediated programmed necrosis. (PubMed, Front Pharmacol) - "We found HDAC3 expression was upregulated in mouse renal tubules after ischemia/reperfusion and cisplatin treatment. In addition, RIPK1 knockdown cell assay signified that RGFP966 targeted RIPK1 and inhibited RIPK1 kinase activity. In summary, these findings established the efficacy of the HDAC3 inhibitor RGFP966 in treating AKI."

Journal • Acute Kidney Injury • Cardiovascular • Fibrosis • Immunology • Inflammation • Nephrology • Renal Disease • Reperfusion Injury • HDAC3 • RIPK1

Endothelial HDAC3 drives retinal pathological angiogenesis via HK2-mediated metabolic reprogramming. (ARVO 2025) - "Methods In vitro, we subjected bovine retinal endothelial cells (BREs) treated with and without the HDAC3 inhibitor RGFP966 to oxygen-glucose deprivation and reperfusion (6h OGD/ 18 h R) to simulate hypoxia...Layman Abstract (optional): Provide a 50-200 word description of your work that non-scientists can understand. Describe the big picture and the implications of your findings, not the study itself and the associated details."

Diabetic Retinopathy • Ophthalmology • Retinal Disorders • Retinopathy of Prematurity • HDAC3 • HK2

Crosstalk between histone acetylation and methylation: Impact on RGC neuroprotection in glaucoma (ARVO 2025) - "Rats were treated with either δ-opioid receptor agonist (SNC-121, 1 mg/kg; i.p), histone deacetylase 3 (HDAC3) inhibitors (MS-275 or RGFP966; 1 mg/kg; i.p), or DNA methylation inhibitor (Decitabine; 1-1.5 mg/kg, i.p injections) daily for 7 days...Layman Abstract (optional): Provide a 50-200 word description of your work that non-scientists can understand. Describe the big picture and the implications of your findings, not the study itself and the associated details."

Epigenetic controller • Glaucoma • Ophthalmology • CXCL8 • DNMT1 • DNMT3A • DNMT3B • HDAC3 • IL6 • TGFB1

Xinyin tablets affect mitophagy and cardiomyocyte apoptosis to alleviate chronic heart failure by regulating histone deacetylase 3(HDAC3)-mediated PTEN induced putative kinase 1(PINK1)/Parkin signaling pathway. (PubMed, J Ethnopharmacol) - "Xinyin tablets have potential as an intervention for CHF by improving mitophagy and inhibiting cardiomyocyte apoptosis through the HDAC3-mediated PINK1/Parkin signaling pathway."

Journal • Cardiovascular • Congestive Heart Failure • Fibrosis • Heart Failure • Immunology • BAX • CASP3 • CASP9 • HDAC3 • PINK1

Histone Deacetylase Inhibitor-Induced Phenotypic Transition of Schwann Cells Into Repair Types: Implications on Repair and Myelination During Nerve Damage [WITHDRAWN] (ARO 2025) - "Schwann cells were treated in vitro with varying concentrations of Valproic Acid, Trichostatin A, RGFP966, and Romidepsin to encompass specific inhibitory effects between specific HDACs. These results suggest that HDACi treatments can induce the phenotypic transition of Schwann cells into repair types by modulating epigenetic regulation of key transcription factors. While high doses may affect cell viability, appropriate dosing of HDACi may temporarily reduce myelination but promote early-stage repair mechanisms. This warrants further in vivo exploration to optimize HDACi treatment protocols for enhancing nerve regeneration and functional recovery."

Epigenetic controller • CNS Disorders

RGFP966 inhibits palmitic acid induced VSMCs phenotypic transition by targeting ATGL. (PubMed, Biochim Biophys Acta Mol Cell Biol Lipids) - "RGFP966 has a protective effect against VSMCs phenotype transitions, potentially related to the regulation of ATGL."

Journal • Cardiovascular • HDAC3

The Two Faces of HDAC3: Neuroinflammation in Disease and Neuroprotection in Recovery. (PubMed, Epigenomics) - "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."

Journal • Review • Cardiovascular • Cerebral Hemorrhage • CNS Disorders • Depression • Hematological Disorders • Inflammation • Mental Retardation • Psychiatry • Vascular Neurology • HDAC3

Kaempferol alleviates myocardial ischemia injury by reducing oxidative stress via the HDAC3-mediated Nrf2 signaling pathway. (PubMed, J Adv Res) - "Our data show that KAE ameliorates cardiac injury by reducing oxidative stress via the HDAC3-mediated Nrf2 signaling pathway in cardiomyocytes."

Journal • Cardiovascular • Myocardial Infarction • Myocardial Ischemia • HDAC3 • NFE2L2

Therapeutic inhibition of Histone deacetylase 3 attenuates chronic EAE (ECTRIMS 2024) - "These findings not only underscore the therapeutic potential of HDAC3 inhibition in autoimmune demyelinating diseases but also shed light on a novel epigenetic mechanism driving autoimmunity and neuroinflammatory pathologies, that expands our knowledge on the pathophysiology of these diseases and may lead to the identification of novel therapeutic targets and strategies."

Epigenetic controller • IO biomarker • CNS Disorders • Immunology • Inflammation • Multiple Sclerosis • CXCL1 • HDAC3 • IDO1 • IL10 • IL17A