rocilinostat (ACY-1215) / Regenacy, BMS, BC Regenacy - LARVOL DELTA

PET Imaging of CD38 and IND enabling studies of [89Zr]Zr-DFO-Isatuximab. (PubMed, Mol Imaging Biol) - "[89Zr]Zr-DFO-Isatuximab showed high specificity to CD38 positive cells, had estimated effective doses comparable to other clinically relevant 89Zr-labeled antibodies, and can be prepared using GMP practices for clinical use."

IO biomarker • Journal • Hematological Malignancies • Multiple Myeloma • Oncology

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

Design, synthesis and anti-cervical cancer activity of aroylpyrrole-based derivatives as potent histone deacetylase 6 inhibitors. (PubMed, RSC Adv) - "10g also showed superior metabolic stability compared to ACY-1215 in a microsomal stability study. In summary, this work highlighted the therapeutic potential of aroylpyrrole-based sHDAC6 inhibitors and provided a valuable lead compound in treating cervical cancer."

Journal • Cervical Cancer • Oncology • Solid Tumor • HDAC1

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

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

ITF6475, a New Histone Deacetylase 6 Inhibitor, Prevents Painful Neuropathy Induced by Paclitaxel. (PubMed, Toxics) - "This study evaluates the HDAC6 inhibitor ITF6475 for its potential to prevent PIPN and compares its effects with ricolinostat, a well-established HDAC6 inhibitor previously studied in cisplatin-induced neuropathy models. PTX-induced reduction in intraepidermal nerve fiber density was significantly prevented in the PTX + ITF6475 (1 mg/kg) group, and PTX-induced increase in neurofilament light levels was reduced in all ITF6475 co-treated groups. These findings support the potential of ITF6475 in preventing small fiber damage in a severe, chronic PIPN model."

Journal • Oncology • Pain • Solid Tumor

Mechanistic Insights into the Anti-Hepatocellular Carcinoma Effects of ACY-1215: p53 Acetylation and Ubiquitination Regulation. (PubMed, Curr Issues Mol Biol) - "This dual modulation restored p53 transcriptional activity, leading to the upregulation of downstream effector molecules associated with cell cycle regulation and apoptosis. Collectively, our findings reveal that ACY-1215 exerts potent anti-HCC effects through coordinated regulation of p53 acetylation and ubiquitination, offering a novel dual-targeting strategy for HCC therapy."

Journal • Hepatocellular Cancer • Oncology • Solid Tumor • Targeted Protein Degradation

Discovery of TNI-97 as a Highly Selective, Orally Bioavailable HDAC6 Inhibitor for the Treatment of Triple-Negative Breast Cancer. (PubMed, J Med Chem) - "ACY-1215 has demonstrated preliminary efficacy in patients with TNBC and HR+/HER2- metastatic breast cancer. TNI-97 exhibited a TGI of 91% in MDA-MB-453 CDX as monotherapy and a TGI of 92% in 4T1 CDA when combined with paclitaxel. The discovery of TNI-97 holds promise for the development of more potent HDAC6 inhibitors as PANoptotic inducers and TNBC drug candidates."

Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • HER-2

Epigenetic targeting of DNA damage response (DDR)-related mechanisms to overcome acquired cisplatin resistance of tumor cells. (PubMed, Biochim Biophys Acta Mol Cell Res) - "We investigated the impact of various classes of histone deacetylase inhibitors (HDACi) (i.e. broad-spectrum HDACi (vorinostat), class I HDACi (entinostat), preferential class IIb HDAC6i (ricolinostat) and dual HDAC class I/IIb inhibitors (HDAC1/6i)) on mechanisms of the DDR using parental (J82WT) and cisplatin (CisPt)-resistant bladder carcinoma cells (J82CisR). This is due to amplification of replicative and transcriptional stress caused by CisPt treatment as well as interference with DDR mechanisms and DNA repair, eventually promoting apoptosis. Thus, epigenetic targeting of DDR-related death pathways by class I HDACi is useful to overcome acquired CisPt resistance of tumor cells."

Journal • Bladder Cancer • Genito-urinary Cancer • Oncology • Solid Tumor • CASP7 • HDAC3 • PARP1

HDAC6 is involved in diabetic nephropathy by regulating TGFβ/Smads and NF-κB signaling pathways. (PubMed, Biochem Pharmacol) - "Our research indicates that HDAC6 is upregulated in DN, and inhibiting HDAC6 activity with ACY1215 or downregulating HDAC6 expression with siRNA can suppress the TGF-β/Smads and NF-κB signaling pathways, thereby reducing renal fibrosis and inflammation...To sum up, this study reveals that HDAC6 is involved in the pathogenesis and progression of DN. Mechanistically, HDAC6 may participate in DN by regulating the TGF-β/Smads and NF-κB signaling pathways through Smad7."

Journal • Diabetes • Diabetic Nephropathy • Fibrosis • Immunology • Inflammation • Nephrology • Renal Disease • HDAC6 • SMAD2 • SMAD7 • TGFB1

IDH1/MDH1 deacetylation activates the cGAS-STING pathway by promoting NETosis in acute liver failure. (PubMed, Int Immunopharmacol) - "IDH1/MDH1 deacetylation activates the cGAS-STING signaling pathway by NETs. The activation of STING promotes pro-inflammatory cytokine production and exacerbates the inflammatory response in LPS/D-gal-induced ALF."

Journal • Hepatology • Inflammation • Liver Failure • IDH1 • IL6 • TNFA

Inhibition of histone deacetylase 6 activity mitigates neurological impairment and post-hemorrhagic hydrocephalus after intraventricular hemorrhage by modulating pyroptosis and autophagy pathways. (PubMed, Fluids Barriers CNS) - "Enhanced autophagy attenuates activation of the NOD-like receptor protein 3 (NLRP3) inflammasome and inhibits neuronal pyroptosis in the acute phase of IVH. HDAC6 plays an important role in regulating the interaction between autophagy and pyroptosis. Ricolinostat treatment significantly attenuated the upregulation of inflammatory factors and neurological impairments induced by pyroptosis in the acute phase of IVH. In addition, ricolinostat effectively reduced excessive autophagy and apoptosis in neurons in the chronic phase and attenuated the formation of PHH."

Journal • CNS Disorders • Hematological Disorders • Inflammation • Ventriculomegaly • NLRP3

Histone deacetylase 6 inhibition abrogates the STAT3-mediated protumoral polarization of M2 TAMs and suppresses the VEGFA/VEGFR2-induced macrophage-breast cancer crosstalk in the tumor microenvironment (ESMO-BC 2025) - "The data was validated in a syngeneic murine breast cancer model. ACY1215 a first-in-class inhibitor of HDAC6, abrogates protumoral polarization of M2 TAMs... Our data suggests HDAC6 plays a pivotal role in driving the protumoral polarization of M2 TAMs. Upon its inhibition, the prometastatic potential of M2 TAMs decreases, disrupting their crosstalk with the breast cancer cells in the TME."

Biomarker • Epigenetic controller • Tumor microenvironment • Breast Cancer • Oncology • Solid Tumor • BRCA • CD163 • IL13 • IL4 • KDR • MRC1 • MYC • STAT3

HDAC6 inhibition ameliorates sensory hypersensitivity and reduces immune cell signatures in the dorsal root ganglia in murine chronic pain models. (PubMed, Mol Pharmacol) - "SIGNIFICANCE STATEMENT: Recent studies highlight the role of histone deacetylase (HDAC)6 in chemotherapy-induced peripheral neuropathy, through mechanisms of action including tubulin acetylation and mitochondrial trafficking. In this study, various murine models of acute and chronic pain are applied to show that inhibition of HDAC6 activity in the periphery, using the clinically tested ACY1215 compound, and genetic inactivation of the Hdac6 gene in the dorsal root ganglia, alleviated mechanical hypersensitivity in male and in female mice through mechanisms that include targeting injury-induced inflammation."

Journal • Preclinical • Immunology • Inflammation • Neuralgia • Pain • Peripheral Neuropathic Pain • HDAC6

Withaferin A combined with ricolinostat: a potent synergistic therapy for cervical cancer through regulating p53 ubiquitination and acetylation. (PubMed, Acta Biochim Biophys Sin (Shanghai)) - No abstract available

Journal • Cervical Cancer • Oncology • Solid Tumor • Targeted Protein Degradation

Histone deacetylase 6 inhibitor affects gut microbiome composition in alcoholic liver mice (APASL 2025) - "By analyzing the gut microbiome of mice, we found that the effects of alcohol and the HDAC6 inhibitor ACY1215 on the composition of the mouse gut microbiome were significant, with some changes in the gut microbiome related to both glucose and lipid metabolism. This sheds some light on the systemic changes caused by HDAC6 inhibitors in vivo and may be involved in the progression of alcohol associated liver disease. Table and Figure:Figure 1.KEGG heatmap Figure 2.eggNOG heatmap"

Epigenetic controller • Preclinical • Hepatology • Infectious Disease • Metabolic Disorders

HDAC6 Inhibitor ACY-1215 Improves Gefitinib-lnduced Liver Injury via Inhibiting TLR4/MyD88/MAPK/ NF-kB Pathway (APASL 2025) - "ACY-1215 could partially reverse the gefitinib-induced liver injury and dysfunction by inhibiting the TLR4/MyD88/MAPK/NFκB signaling pathway. Table and Figure:Figure 1.AML 12 and MIHA cells were co-cultured with 30μM gefitinib and different concentrations of ACY1215 for 24 hours. (A) Cell viability."

Hepatology • Liver Failure • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • IL6 • MYD88 • NFKBIA • TLR4 • TNFA

Inhibition of histone deacetylase 6 alleviates neuropathic pain via direct regulating post-translation of spinal STAT3 and decreasing downstream C-C Motif Chemokine Ligand 7 synthesis. (PubMed, J Neuroinflammation) - "These findings demonstrate that ACY-1215 mitigates neuropathic pain by modulating STAT3 acetylation/phosphorylation and suppressing HDAC6/STAT3-driven CCL7 and cytokine release. This study underscores the role of the HDAC6/STAT3/CCL7 signaling axis in neuropathic pain and highlights the therapeutic potential of HDAC6 inhibitors for pain management."

Journal • Immunology • Neuralgia • Oncology • Pain • HDAC6 • IL1B • STAT3 • TNFA

VHL ameliorates arecoline-induced oral submucosal fibrosis by promoting HDAC6 ubiquitination and blocking NF-κB pathway. (PubMed, Sci Rep) - "HDAC6 selective inhibitor ACY-1215 inhibited the NF-κB signaling pathway. VHL attenuated arecoline-induced OSF by inhibiting the ubiquitination of HDAC6 and blocking NF-κB pathway. As a result, our study offers new perspectives into the discovery of novel tactics that can be employed against OSF."

Journal • Fibrosis • Immunology • Oncology • Targeted Protein Degradation • Von Hippel-Lindau Syndrome • HDAC6

Targeting the HDAC6/Hint2/MICU1 axis to ameliorate acute liver failure via inhibiting NETosis. (PubMed, Life Sci) - "Our findings recognized the HDAC6/Hint2/MICU1 axis as a novel pathway in neutrophils, the inhibition of which intercepts mCa2+ overload and mtROS accumulation, thereby reducing NETosis and facilitating liver recovery during ALF."

Journal • Hepatology • Inflammation • Liver Failure

Discovery of Novel and Highly Potent Dual PD-L1/Histone Deacetylase 6 Inhibitors with Favorable Pharmacokinetics for Cancer Immunotherapy. (PubMed, J Med Chem) - "Moreover, HP29 exhibited significant in vivo antitumor efficacy in a melanoma tumor model with a greater tumor growth inhibition (TGI) (65.5%) than that of NP19 (43.2%), ACY-1215 (45.6%), and the combination group (53.9%). Mechanistically, the percentages of tumor-infiltrating lymphocytes (TILs) in the HP29-treated tumor tissues were significantly higher than the combination group or PD-L1 inhibitor monotherapy group, suggesting potential synergistic antitumor immune effects. Collectively, HP29 represents a novel PD-L1/HDAC6 dual inhibitor deserving further investigation as a potential cancer immunomodulating agent."

Journal • PK/PD data • Melanoma • Oncology • Solid Tumor

Polymer-based nanodrugs enhance sonodynamic therapy through epigenetic reprogramming of the immunosuppressive tumor microenvironment. (PubMed, J Control Release) - "In this study, we developed tumor microenvironment-responsive nanoparticles (GdNPs) to enhance SDT effectiveness through epigenetic reprogramming of the TME by encapsulating the sonosensitizer chlorin e6 (Ce6) and the histone deacetylase 6 (HDAC6) inhibitor Ricolinostat (Ric) (GdNPs/Ce6-Ric)...Furthermore, GdNPs/Ce6-Ric minimized lung metastases by not only improving systemic immune responses but also inhibiting TGFβ-induced epithelial-mesenchymal transition (EMT) of tumor cells through the blockade of α-tubulin deacetylation. Thus, GdNPs/Ce6-Ric-based epigenetic modulation of the immunosuppressive TME offers a promising approach to enhance the efficacy of SDT in treating TNBC."

Biomarker • Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • HDAC6 • TGFB1

ACY1215 Exerts Anti-inflammatory Effects by Inhibition of NF-κB and STAT3 Signaling Pathway to Repair Spinal Cord Injury. (PubMed, Biol Pharm Bull) - "In summary, ACY1215 can inhibit the NF-κB and STAT3 signaling pathways in astrocytes, reduce inflammation and ameliorate SCI. Our results provide a novel strategy for the treatment of SCI."

Journal • CNS Disorders • Oncology • Orthopedics • GFAP • IL1B • IL6 • TNFA

IDH1/MDH1 deacetylation promotes NETosis by regulating OPA1 and autophagy. (PubMed, Int Immunopharmacol) - "IDH1/MDH1 deacetylation promoted NETosis by regulating autophagy and OPA1 in vitro. The regulation of neutrophil autophagy on NETosis during IDH1/MDH1 deacetylation might be masked in mice. ACY1215 might attenuate NETosis by regulating neutrophil autophagy, which alleviated ALF aggravated by IDH1/MDH1 deacetylation."

Journal • Hepatology • Liver Failure • BECN1 • IDH1

Ricolinostat, an HDAC6 inhibitor, suppresses hypoxia-induced responses and M2 polarization of macrophages in triplenegative breast cancer by modulating HIF-1α pathway (KSMO 2024) - No abstract available

Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • HIF1A