mocetinostat (MGCD0103) / Otsuka, BMS - LARVOL DELTA

Structure-guided identification of histone deacetylase 11 inhibitors for targeted chemotherapy through long-timescale molecular dynamics simulation. (PubMed, J Mol Model) - "Mocetinostat exhibited the highest binding affinity toward HDAC11 (-8.70 kcal/mol) with acceptable pharmacokinetic properties (LogP: 2.25; TPSA: 99.11 Å2), while Belinostat showed the safest toxicity profile (LD50: 6000 mg/kg; Class 6)...Comparative MD analyses over 500 ns revealed high structural stability for the Nanatinostat-HDAC11 and Resminostat-HDAC11 complexes by lower RMSD, reduced residue fluctuations, and more stable hydrogen bond interactions...A total of 3.5 µs of molecular dynamics simulations were performed, including a 500 ns production run and triplicate 100 ns validation runs for each complex. MD trajectory analyses, including RMSD, RMSF, radius of gyration, solvent-accessible surface area, hydrogen bond analysis, and kernel density estimation, were used to evaluate structural stability and interaction dynamics."

Journal • Oncology • HDAC1 • HDAC11

Cancer-associated KBTBD4 mutations induce differentiation defects and confer a unique therapeutic vulnerability. (PubMed, Cancer Gene Ther) - "Using our HSPC model, we demonstrated that the class I HDAC inhibitor mocetinostat alleviated differentiation defects caused by KBTBD4 mutations. Together, these findings reveal the tumorigenic mechanism of KBTBD4 mutations and uncover therapeutic vulnerabilities that may be exploited for clinical applications."

Journal • Brain Cancer • Embryonal Tumor • Oncology • Solid Tumor • Targeted Protein Degradation

Histone deacetylase inhibitors enhance the amoebicidal activity of amphotericin B against Naegleria fowleri. (PubMed, Int J Parasitol Drugs Drug Resist) - "Class-specific HDACis, including class I inhibitors MS275 and MGCD0103 and a class II inhibitor MC1568, showed minimal effects on trophozoite viability...These combination treatments also exhibited low cytopathic effects on human brain tumor cells. These findings suggest that SAHA and JNJ, particularly in combination with AmB, hold promise as therapeutic candidates against N. fowleri infection while potentially mitigating the severe side effects associated with AmB."

Journal • Brain Cancer • CNS Disorders • Infectious Disease • Oncology • Solid Tumor

Pembrolizumab (Immunotherapy Drug) in Combination With Guadecitabine and Mocetinostat (Epigenetic Drugs) for Patients With Advanced Lung Cancer. (clinicaltrials.gov) - P1 | N=28 | Active, not recruiting | Sponsor: Memorial Sloan Kettering Cancer Center | Trial completion date: Jul 2026 ➔ Jul 2027 | Trial primary completion date: Jul 2026 ➔ Jul 2027

Trial completion date • Trial primary completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Three High Throughput Compatible Cell-Based Assays for Identifying Small Molecule JAG1 Upregulators for Alagille Syndrome. (PubMed, SLAS Discov) - "Entinostat, Mocetinostat, and Chidamide were consistently identified as the most potent JAG1 upregulators across all assays. These complementary assays provide a flexible platform for identifying small molecule modulators of gene dosage and may be broadly applicable to drug discovery efforts targeting haploinsufficiency diseases."

Journal • JAG1

Mocetinostat With Vinorelbine in Children, Adolescents & Young Adults With Refractory and/or Recurrent Rhabdomyosarcoma (clinicaltrials.gov) - P1 | N=14 | Active, not recruiting | Sponsor: Jonsson Comprehensive Cancer Center | N=38 ➔ 14 | Trial completion date: May 2027 ➔ Dec 2027 | Trial primary completion date: May 2026 ➔ Dec 2026

Enrollment change • Trial completion date • Trial primary completion date • Oncology • Rhabdomyosarcoma • Sarcoma • Solid Tumor

Integrative spatiotemporal transcriptomics identifies a liver metastasis-related initial cell population associated with the SEMA3A-NRP1 axis in pancreatic ductal adenocarcinoma. (PubMed, J Transl Med) - "At single-cell resolution, this study characterizes the LMIC population in PDAC and implicates a CAF-associated SEMA3A-NRP1 signaling axis within their spatial and functional microenvironmental niches. These findings provide a refined conceptual framework for the development of prospective targeted strategies aimed at disrupting early microenvironmental cross-talk associated with PDAC liver metastasis."

IO biomarker • Journal • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • ACACA • CAFs • FASN • NRP1 • NRP2 • SEMA3A • YY1

MACHINE LEARNING AND MECHANISTIC MODELLING-BASED RECONSTRUCTION OF HEMATOPOIETIC TRAJECTORIES BY CSTAR REVEALS NOVEL LEUKEMIA DIFFERENTIATION STRATEGIES (EHA 2026) - "This causal network highlighted key signaling nodes predicted to drive transition to a mature myeloid phenotype, specifically, All-trans retinoic acid (ATRA), mocetinostat (class I HDAC inhibitor), and Ro-3306 (CDK2 inhibitor)...We are currently analyzing RNA-seq data to determine drug combination effects on cSTAR-predicted differentiation networks. Summary/Conclusion We provide a quantitative and mechanistic reconstruction of human hematopoietic differentiation and show that cSTAR can predict novel actionable strategies to potentially overcome AML differentiation arrest."

Machine learning • Acute Myelogenous Leukemia • Acute Promyelocytic Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia

Identification of novel therapeutic agents using patient-derived organoids in HCC (EASL 2026) - "Among them, dinaciclib, homoharringtonine, volasertib, mocetinostat, and daunorubicin, have bene already reported as effective on HCC...Among standard treatments, only sorafenib inhibited HCC-PDOs...In keeping with this, osimertinib, another drug highlighted by the screening on HCC-PDO and currently used for EGFR-mutant lung cancer, has been reported as effective also in HCC (J... The identification of dinaciclib and homoharringtonine as potent agents aligns with recent literature on novel HCC drugs, and validates the robustness of our approach and the potential of our results. Moreover, our results disclosed a significant potential for some drug repurposing. A recent study showed that cerinitib, a drug targeting ALK mutation in advanced non-small cell lung cancer, inhibits β-catenin mutated HCC via non-canonical WNT pathway independent of ALK (J Hep Reports, 2025)."

Clinical • Hepatocellular Cancer • Lung Cancer • Non Small Cell Lung Cancer • ALK • CTNNB1 • EGFR

Zinc Affinity of Benzamide-Based Histone Deacetylase Inhibitors: A DFT Study. (PubMed, Molecules) - "Clinically relevant representatives include Chidamide, Entinostat, Mocetinostat, Zabadinostat, and Tacedinaline. Interestingly, calculated substitution free energies differed by less than ± 2 kcal.mol-1, indicating nearly identical intrinsic Zn2+ affinities across the series. These results suggest that the ZBG contributes similarly to metal coordination across all BBHDACi, whereas the overall binding strength is mainly governed by interactions of the linker and cap regions rather than by the conserved zinc-binding group itself."

Journal • Oncology

Mocetinostat Ameliorates Pathological Cardiac Hypertrophy via Suppression of Ferroptosis Through Nrf2 Pathway. (PubMed, Pharmazie) - "This study demonstrates that mocetinostat attenuates pathological cardiac hypertrophy by inhibiting ferroptosis through activation of the Nrf2 pathway . These findings indicate the potential of mocetinostat as a therapeutic strategy for delaying heart failure progression."

Journal • Cardiovascular • Congestive Heart Failure • Fibrosis • Heart Failure • Immunology • GPX4 • HMOX1 • SLC7A11

Cardiac HDAC3 Disruption Contributes to HDAC Inhibitor-Induced QT Prolongation. (PubMed, Cells) - "Moreover, a single dose of HDAC inhibitors, romidepsin or mocetinostat, caused reversible QT prolongation in mice. Consistent with these findings, HDAC inhibitor treatment altered the expression of potassium channel genes, with a predominant downregulation of multiple Kcn family members, including Kcnq1, Kcnh2, and Kcnip2. These findings establish HDAC3 enzymatic activity as a key regulator of cardiac repolarization and provide mechanistic insight into HDAC inhibitor-associated cardiotoxicity."

Journal • Cardiovascular • Oncology • HDAC3 • KCNH2 • KCNQ1OT1

Rational Design, Optimization and Bioinformatic Analysis of Anti-PD-L1 Peptide Conjugated Mocetinostat Prodrug Nanoparticles for Predictive Cancer Chemoimmunotherapeutic Efficacy. (PubMed, Pharm Res) - "PD-NPs showed remarkable structural stability, enzyme-responsive activation, and favorable biocompatibility, indicating their potential as a predictive cancer chemoimmunotherapy."

Journal • Hematological Disorders • Lung Cancer • Oncology • Solid Tumor • CTSB

Class I HDAC Inhibition Enhances the Stem-Like Memory Properties of CRISPR-Engineered CAR T Cells in Neuroblastoma (ASGCT 2026) - "Results Compared to untreated GD2 TRAC-CAR T cells, Chidamide and Mocetinostat increased the stem cell memory markers (CD62L+/CCR7+/IL-7Rα+). In vivo, Chidamide uniquely enhanced the persistence, and naïve phenotype of the GD2 TRAC-CAR T cells without upregulating exhaustion markers (PD- 1/LAG3). Conclusion These findings suggest that in the management of treatment-resistant pediatric solid tumors, utilizing Chidamide during the manufacturing of CRISPR-engineered CAR T cells may enhance their persistence while retaining a naïve phenotype."

CAR T-Cell Therapy • IO biomarker • Neuroblastoma • Solid Tumor • CCR7 • LAG3

CREB–mediated pharmacologic antagonism is associated with adaptive escape from MAPK inhibition in melanoma (SID 2026) - "To identify antagonistic compounds, we subjected 5 BRAF* melanoma lines to a high-throughput screen of 1,600 broad-spectrum FDA-approved and advanced preclinical drugs, co-administered with dabrafenib + trametinib (D+T; 4.0/0.4 nM)...The top 5 ranking antagonistic drugs were Mocetinostat (E=0.92), CP673451 (E=0.88), Axitinib (E=0.76), Amuvatinib (E=0.74), and BX-795 (E=0.74)...Notably, this subset included 14 mechanistically related platelet-derived growth factor receptor inhibitors (PDGFRI: CP673451, Amavadin, Axitinib, Crenolanib, Nintedanib, Sorafenib, Linifanib, Tivozanib, Imatinib, Masitinib, Pazopanib, Motesanib, Sunitinib)...Comparative phosphokinome profiling across the 3 cell lines identified CREB phosphorylation at S133 as a conserved event, robustly suppressed by D+T but selectively rescued by PDGFRi co-treatment. Together, these data identify PDGFR inhibitors as a reproducible source of antagonism to BRAF+MEK-targeted therapy and nominate CREB phosphorylation..."

Melanoma • Solid Tumor

Discovery and validation of effective combination therapies targeting cell state-specific master regulator vulnerabilities by network-based protein activity inference in diffuse midline glioma (AACR 2024) - "Candidate drugs predicted by OncoTarget (inhibitors of individual MRs) and OncoTreat were distinct across the cell states, and we selected five drugs targeting the OPC/cycling-like cells (Trametinib, Dinaciclib, Avapritinib, Mocetinostat, and Etoposide), and four drugs targeting the AC-like cells (Ruxolitinib, Venetoclax, Napabucasin, Larotrectonib) for further validation as these states comprised most tumor cells across patients.We generated single-cell RNAseq for 95,687 cells after 5 days of treatment with either vehicle control (n = 4) or candidate drug (n = 2-3/drug) in subcutaneous SU-DIPG-17 mouse models. Notably, the combination of drugs targeting OPC/cycling-like and AC-like cells (i.e. Trametinib+Ruxolitinib and Avapritinib+Venetoclax) showed significantly lower tumor volumes after 2 weeks of treatment as compared to vehicles or each drug alone, and significant survival differences for some combinations. This work provides a precision medicine platform to..."

Combination therapy • Brain Cancer • CNS Tumor • Diffuse Midline Glioma • Glioma • Oncology • Solid Tumor

PRAISE-MR trial (clinicaltrialsregister.eu) - P4 | N=110 | Completed | Sponsor: Ziekenhuis Oost Limburg | Active, not recruiting ➔ Completed

Trial completion • Cardiovascular • Congestive Heart Failure • Heart Failure

Class I HDAC inhibition enhances the stem-like memory properties of CRISPR-engineered CAR T cells in neuroblastoma. (PubMed, Mol Ther Oncol) - "Compared to untreated GD2 TRAC-CAR T cells, chidamide and mocetinostat increased the stem cell memory marker expression (CD62L+/CCR7+/IL-7Rα+). Chidamide induced a fragmented mitochondrial morphology and, in vivo, enhanced the persistence and naive phenotype of the GD2 TRAC-CAR T cells without upregulating exhaustion markers (PD-1/LAG3). These findings suggest that in the management of treatment-resistant pediatric solid tumors, utilizing chidamide during the manufacturing of CRISPR-engineered CAR T cells may enhance their persistence while retaining a naive phenotype."

IO biomarker • Journal • Neuroblastoma • Oncology • Pediatrics • Solid Tumor • CCR7 • LAG3 • PD-1 • SELL

Class I histone deacetylases and their inhibitors as targets to modulate cellular senescence in osteoarthritis. (PubMed, Geroscience) - "Overall, our findings demonstrate a key role of Class I HDACs in regulating chondrocyte survival and ECM gene expression. Mocetinostat holds promise as a senolytic therapeutic for OA and potentially other aging-related musculoskeletal disorders."

Journal • Immunology • Inflammation • Musculoskeletal Diseases • Osteoarthritis • Pain • Rheumatology • HDAC1 • HDAC2

Enhancement of antigen presentation restores immune recognition in rhabdomyosarcoma (AACR 2026) - "RMS cell lines (n=9) were treated with IFN-γ and clinically relevant drugs, decitabine (DAC), mocetinostat, and tazemetostat. Pediatric tumors show distinct patterns of antigen presentation, such as high MHC-I in alveolar soft part sarcoma and low expression in RMS, though individual tumor subtypes exhibit internal variability. IFN-γ and epigenetic agents restore antigen presentation, including increased NLRC5 expression. Pharmacological treatment and NLRC5 restoration enhanced antigen presentation and sensitized RMS PDX to TCR mediated T-cell cytotoxicity."

IO biomarker • Alveolar Soft Tissue Sarcoma • Oncology • Rhabdomyosarcoma • Sarcoma • Solid Tumor • HLA-A • HLA-B • HLA-C • IFNG • NLRC5 • PRAME

Zeb1 downregulation sensitizes pancreatic cancer-associated fibroblasts to killing by oncolytic reovirus through upregulation of the reovirus receptor junction adhesion molecule A (AACR 2024) - "Additionally, the clinically approved drug Mocetinostat, previously described to inhibit Zeb1, upregulated JAM-A expression on CAFs and increased cell lysis by reovirus. Altogether, our data show that Zeb1 is a strong negative regulator of JAM-A expression on fibroblasts and that Zeb1 inhibition can sensitize CAFs to reovirus-induced cell death. This research provides a rationale for combining Zeb1 inhibitory drugs with oncolytic reovirus treatment to improve killing of CAFs, which in turn could boost overall tumor eradication."

Oncolytic virus • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Solid Tumor • CAFs • F11R • FGFR1 • ZEB1

Unraveling SMARCA1's role in cancer progression, drug resistance, and muscle differentiation through EMT-related signaling, TGF-β pathway, and key transcription factors SNAI1 and EGR1 (AACR 2025) - "Further cell survival assays revealed that SMARCA1 KO cells are particularly sensitive to the HDAC2 inhibitor Mocetinostat and the MEK inhibitor Trametinib, proposing that targeting SMARCA1 in combination with HDAC2 or MEK inhibition could be an effective therapeutic approach for RMS...Additionally, SMARCA1 KO cells responded differently to both canonical and non-canonical TGF-β pathway inhibitors, including SB505124 (TGFBR1 inhibitor), the PI3K-mTOR inhibitor Dactolisib, and Withaferin A (NF-κB inhibitor). Notably, these TGF-β pathway inhibitors effectively overcame resistance in ARMS cells with SMARCA1 expression, exposing specific vulnerabilities in these otherwise resistant cells. Together, our findings suggest that targeting both canonical and non-canonical TGF-β pathways, alongside SMARCA1, presents promising therapeutic strategies for overcoming drug resistance and potentially limiting RMS progression."

Oncology • Rhabdomyosarcoma • Sarcoma • Solid Tumor • CDK4 • EGR1 • HDAC2 • MYCN • Myogenin • NFKB2 • PPP2R5C • PTEN • SMARCA4 • SMARCD3 • SNAI1 • TGFB1 • TGFBR1

Suppression of antigen presentation in pediatric rhabdomyosarcoma (AACR 2024) - "Epigentic drugs targeting DNA methylation (decitabine), EZH2 (tazemetostat), Class I/IV HDACs (mocetinostat), and LSD1 (GSK-LSD1) were used at sub-cytotoxic doses on RMS cell lines (n=10) and analyzed for surface MHC-I expression with flow cytometry and gene expression. RMS cell line models exhibited a range of MHC-I expression with most having low or undetectable MHC-I expression, similar to that of a known MHC-I negative tumor type MYCN-amplified neuroblastoma. Exome sequencing of RMS tumors showed no evidence of loss-of-function alterations in essential antigen processing and presentation (APP) pathway genes. Gene expression profiling by RNAseq and western blotting, however, revealed an absence of core APP genes in many RMS tumors and cell lines."

Clinical • IO biomarker • Late-breaking abstract • Tumor mutational burden • Neuroblastoma • Oncology • Rhabdomyosarcoma • Sarcoma • Solid Tumor • CD8 • MYCN • PRAME • TMB

Developmental states determine intrinsic resistance to immunotherapy in pediatric rhabdomyosarcoma [WITHDRAWN] (AACR 2025) - "Epigenetic drugs targeting DNA methylation (decitabine), EZH2 (tazemetostat), Class I/IV HDACs (mocetinostat), and LSD1 (GSK-LSD1) were used at sub-cytotoxic doses on RMS cell lines (n=10). RMS cell lines, PDXs, and tumors exhibited a range of MHC-I expression, with most having low or undetectable surface expression. Exome sequencing of RMS tumors did not detect frequent genomic alterations in the APM pathway genes. The state of development in RMS tumors was associated with the APM gene signature and surface MHC-I expression with dominant myoblast cell states negatively correlating with APM."

Clinical • IO biomarker • Tumor mutational burden • Oncology • Rhabdomyosarcoma • Sarcoma • Soft Tissue Sarcoma • Solid Tumor • CD8 • PRAME • TMB

EXPRESS: Mocetinostat (MGCD0103) induced autophagy in SKBR-3 breast cancer cells by regulating ROS/MAPK pathway. (PubMed, J Investig Med) - "Mocetinostat suppressed the growth of breast cancer cells in vitro through a ROS-mediated autophagy mechanism using the MAPK pathway. Investigating the mechanism of mocetinostat may provide a novel therapeutic approach for breast cancer treatment."

Journal • Breast Cancer • Oncology • Solid Tumor • ATG5