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

High-Throughput Screen to Find Small Molecules That Can Modulate Adenine Base Editor Efficiency for CFTRR553X (NACFC 2026) - "Preliminary studies using reporter signal outputs assessed small molecules, such as chloroquine, ricolinostat, and nexturastat A, that affect intracellular trafficking and epigenetic regulation. This study's goal is to identify compounds that modulate base editing efficiency and mechanisms within the cell that govern base editor activity for translational applications. Promising candidates will then be validated in vivo using cystic fibrosis mouse models we have developed that carry the same human CFTR sequence in the mouse CFTR genome, treated with LNP or eVLP editing platform via systemic or airway-targeted routes. In vivo efficacy will be assessed by deep sequencing of genomic DNA from disease-relevant tissues to quantify on-target editing efficiency, dose– response relationships, and tissue distribution of editing outcomes."

Cystic Fibrosis • Genetic Disorders • Immunology • Respiratory Diseases • CFTR

HDAC6 inhibition alleviates dexamethasone-induced skeletal muscle atrophy and enhances UCP3-associated redox homeostasis. (PubMed, Free Radic Biol Med) - "This study identifies UCP3-associated redox homeostasis as an important downstream mechanism linking HDAC6 inhibition to protection against dexamethasone-induced muscle atrophy. In C2C12 myotubes, UCP3 was required for the protective effects of HDAC6 knockdown and ACY-1215, whereas UCP3 overexpression was sufficient to attenuate dexamethasone-induced myotube atrophy. ACY-1215 also alleviated dexamethasone-induced muscle atrophy in mice, although the UCP3 dependence of this in vivo effect remains to be determined."

Journal • Muscular Atrophy • Targeted Protein Degradation • FBXO32 • GPX1 • GPX4 • SOD2 • TFAM

Targeting HDAC6 mitigates diabetic nephropathy through modulation of oxidative stress, inflammatory pathways, and apoptotic signaling. (PubMed, Biochem Pharmacol) - "Male Sprague-Dawley rats injected STZ (60 mg/kg, i.p.) to induce diabetes, followed by treatment with the selective HDAC6 inhibitors tubastatin A (TubA, 30 mg/kg/day, i.p.) or ACY-1215 (30 mg/kg/day, i.p.) for 3 weeks after confirmation of hyperglycemia...Mechanistically, HDAC6 inhibition restored antioxidant defenses, as evidenced by increased expression of nuclear factor-erythroid 2-related factor 2 (Nrf2), Heme oxygenase 1 (HO-1), sirtuin-3 (SIRT3), and MnSOD, reduced oxidative stress markers including advanced glycation end-products (AGEs), malondialdehyde (MDA), and 8-Hydroxy-2-deoxyguanosine (8-OHdG), suppressed Interleukin-1 beta (IL-1β) and Interleukin 6 (IL-6), attenuated apoptosis, and inhibited fibrosis and epithelial-mesenchymal transition by modulating the expression of transforming Growth Factor Beta 1 (TGF-β1), vimentin, α-Smooth muscle actin (α-SMA), and E-cadherin. Collectively, these findings demonstrate that HDAC6 inhibition exerts potent..."

Journal • Diabetes • Diabetic Nephropathy • Fibrosis • Immunology • Inflammation • Metabolic Disorders • Nephrology • Renal Disease • CDH1 • HMOX1 • IL1B • IL6 • KIM1 • LCN2 • NFE2L2 • SELENBP1 • SIRT3 • SOD2 • TGFB1 • VIM

Preclinical and clinical efficacy of the HDAC6 inhibitor ricolinostat in combination with BCR pathway inhibitors in relapsed/refractory chronic lymphocytic leukemia. (PubMed, Blood Cancer J) - No abstract available

Journal • Preclinical • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology

Preclinical and clinical efficacy of the HDAC6 inhibitor ricolinostat in combination with BCR pathway inhibitors in relapsed/refractory chronic lymphocytic leukemia (Nature) - "In cells from five additional CLL patients, ricolinostat monotherapy demonstrated superior cytotoxicity over idelalisib and ibrutinib, reducing median viability by 33% and 43.8% more at 48-hour drug incubation, respectively. Combining ricolinostat with either idelalisib or ibrutinib significantly inhibited cell viability, achieving median reductions in viability by 12.4% and 15.4% more at 48-hours, respectively, compared to ricolinostat monotherapy. In cells from seven CLL patients, ricolinostat demonstrated significantly greater proliferation inhibition than idelalisib or ibrutinib, with median differences of 8.4% and 16.1%, respectively...Overall, the data highlight the therapeutic potential of concurrently targeting epigenetic regulation and BCR signaling pathways in CLL. Further investigations in a larger cohort of patients are needed to validate the clinical efficacy and mechanistic impact of HDAC6 inhibition in CLL."

Preclinical • Chronic Lymphocytic Leukemia

Inhibition of HDAC6 and ROCK Kinase Impairs Macrophage Migration and Proliferation (ATC 2026) - "Our research confirms that combined treatment significantly alters macrophage properties and could thus be an effective strategy for reducing fibrosis in post-transplantation patients and other, fibrotic-related diseases."

Fibrosis • Immunology • Inflammation • Transplant Rejection • CTTN • RHOA

Activated hepatic stellate cell membrane-camouflaged nanomedicine enables targeted HDAC6 inhibition for liver fibrosis therapy. (PubMed, J Control Release) - "To enable selective HDAC6 inhibition in activated HSCs, we developed an activated HSC membrane-camouflaged PLGA nanomedicine (PLGA-Ric@HSCM) loaded with the HDAC6 inhibitor ricolinostat (Ric)...Compared to PLGA-Ric, PLGA-Ric@HSCM shows a more pronounced reduction in fibrosis burden and improved hepatic pathology across etiologically distinct models. Together, PLGA-Ric@HSCM provides a biomimetic, HSC-targeted strategy to reprogram acetylation homeostasis via HDAC6 inhibition and consequently mitigate liver fibrogenesis."

Journal • Fibrosis • Hepatology • Immunology • Liver Cirrhosis • Liver Failure • ATF2 • JUN • TGFB1

Selective HDAC6 inhibition perturbs autophagy and enhances integrated stress response-mediated immunogenic apoptosis in chronic myeloid leukemia. (PubMed, Biomed Pharmacother) - "The selective HDAC6 inhibitor 7b induced sustained α-tubulin acetylation at lower concentrations than ricolinostat or nexturastat A. 7b reduced primary CML PBMC viability while sparing healthy PBMCs and was active in vivo...ISR activation occurred downstream of the autophagy disruption: rapamycin attenuated ISR activation, whereas ATG7 silencing intensified ISR signaling and apoptosis...The combination elicited immunogenic cell death markers: calreticulin exposure, ATP and HMGB1 release, elevated TNF-α, and reduced IL-8. These findings identify HDAC6-driven autophagy as a therapeutically exploitable vulnerability in CML that, when combined with asciminib, triggers ISR-dependent immunogenic apoptosis."

Journal • Chronic Myeloid Leukemia • Hematological Malignancies • Leukemia • Oncology • ATF4 • ATG7 • BCL2L1 • BCR • CALR • CASP10 • CASP3 • CASP9 • CXCL8 • HMGB1 • MCL1 • TNFA

ACY-1215 ameliorates experimental colitis by inhibiting dendritic cell maturation and Th1/Th17 responses. (PubMed, Inflamm Res) - "These findings support selective HDAC6 inhibition as an immunoepigenetic strategy that restrains dendritic cell-driven T-cell responses and promotes mucosal homeostasis, highlighting ACY-1215 as a mechanism-based therapeutic candidate for inflammatory bowel disease."

Journal • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease

HDAC Inhibition Induces Transient Phenotypic Inertia in Dormant OCCC Spheroids by Derepression of Cell Cycle Genes. (PubMed, Cells) - "Comparative pathway analysis identified preferential de-repression of a G2/M checkpoint gene program in 105C spheroids upon Entinostat treatment when compared directly to the KOC-7c spheroids. Our results suggest that the utility of HDACi in OCCC is highly context-dependent."

Journal • Clear Cell Carcinoma • Oncology • Ovarian Cancer • Solid Tumor • ARID1A

Mechanistic basis of resistance to HDAC6 inhibitors reveals proteasome inhibition as a rational combination strategy in breast cancer (AACR 2026) - "These findings identify elevated proteasomal capacity as a key driver of resistance to HDAC6 inhibitors, supporting a therapeutic strategy that combines HDAC6 and proteasome inhibition to overcome resistance in breast cancer."

Breast Cancer • Oncology • Solid Tumor

Epigenetic remodeling via HDAC6 inhibition amplifies anti-tumoral immune responses in myeloid leukemia cells. (PubMed, Cell Death Dis) - "Moreover, an extended drug screening analysis identified Cytarabine and Clofarabine as significantly synergizing with HDAC6 inhibitor (Ricolinostat) in myeloid leukemia cell lines and in patient-derived xenograft (PDX) cells, while showing limited synergy in lymphoid leukemia cell lines, PDX, or healthy control cells. These findings suggest that HDAC6 represents a promising therapeutic target in myeloid lineage-derived leukemia cells by simultaneously enhancing immune activation and increasing chemosensitivity."

Journal • Hematological Malignancies • Leukemia • Oncology • CD8 • HDAC6 • LAMP1 • TNFA

Super-Enhancer-Driven TCF4 Orchestrates Neuroblastoma Metastasis by Sphingolipid-Dependent Membrane Remodeling and ITGB1-FAK Activation. (PubMed, Neuro Oncol) - "Our findings indicate that SE-driven TCF4 can orchestrate metastatic transcriptional networks to maintain NB malignancy and propose ACY-1215 as a translational therapeutic candidate for clinical intervention."

Journal • Neuroblastoma • Oncology • Solid Tumor • ITGB1 • TCF4

First-in-Class Potent, Dual HDAC6/Proteasome Inhibitors Lacking a Hydroxamic Acid Motif: Discovery of Novel Anti-Multiple Myeloma Agents. (PubMed, ACS Med Chem Lett) - "Motivated by promising clinical trial data for the combination of the histone deacetylase 6 (HDAC6) inhibitor ricolinostat with the proteasome inhibitor bortezomib in relapsed/refractory multiple myeloma (MM) patients, we engineered dual HDAC6/proteasome inhibitors...Deploying the HDAC6-selective phenyl-4-hydroxamic acid motif, and O-carbamoylated hydroxamates as hydroxamic acid surrogates, then grafting to the electrophilic boronic acid warhead of bortezomib/ixazomib, we discovered several dual HDAC6/proteasome inhibitors that were potent in cell-free assays, inhibiting the chymotrypsin-like (CL) proteasomal activity on par with that of bortezomib, and many compounds demonstrated selectivity for HDAC6 over HDAC1 as predicted. Moreover, several dual HDAC6/proteasome inhibitors were submicromolar inhibitors of MM cell growth. Of particular interest, AMC-3-030 with an O-(N-phenylcarbamoyl)-hydroxamate ZBG emerged as an exciting lead for further studies."

Journal • Hematological Malignancies • Multiple Myeloma • Oncology • HDAC1

Acetylation of Hint2 mitigates acute liver failure by suppressing neutrophil chemotaxis and NETosis through maintaining mitochondrial calcium and protein homeostasis. (PubMed, Int Immunopharmacol) - "Acetylation of Hint2 at K119 preserves mitochondrial calcium and protein homeostasis, thereby limiting neutrophil chemotaxis and NETosis in ALF. Targeting Hint2 acetylation represents a promising therapeutic strategy to mitigate neutrophil-driven liver injury."

Journal • Hepatology • Inflammation • Liver Failure • HINT2

Role of HDAC6 in carcinomas. (PubMed, Discov Oncol) - "To date, research on HDAC6 in tumors has firmly established its value as a potential therapeutic target, with specific inhibitors (e.g., ACY-1215 and Tubastatin A) demonstrating significant antitumor activity in preclinical studies and several clinical trials. Focused on the implications of HDAC6 in tumors, this review not only highlights its distinct functions compared to other HDAC family members but also integrates previously unreported mechanisms of action (e.g., HDAC6 cooperates with NEDD8/p62 to sustain proteostasis) and clinical translation perspectives. Collectively, it presents an innovative review that provides valuable references for subsequent basic research and clinical practice of HDAC6-targeted tumor therapy."

Journal • Review • Oncology • Targeted Protein Degradation • UBB

ACY-1215 and bortezomib cooperatively disrupt NOTCH3 signaling and induce anti-tumor effects in T-ALL models. (PubMed, Biomark Res) - No abstract available

Journal • Oncology • T Acute Lymphoblastic Leukemia • NOTCH3

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