ITF3756 / Italfarmaco - LARVOL DELTA

Highly selective HDAC6 inhibitors: Are they the answer for immunomodulation? (AACR 2026) - "Among HDAC6i, hydroxamic acid-based compounds such as ITF3756 and ACY-1083 have shown high potency and selectivity, although off-target effects resulting from the binding to other HDACs or non-HDAC targets cannot be ruled out at high concentrations...However, only the CRBN-linked PROTAC reduced cytokine production in monocytes, an effect that we determined being attributable to the pomalidomide recruiter itself...Furthermore, our results point-out that the effects of degraders in an immunological context may be influenced by their recruiter moiety, rather than being solely driven by target degradation. Overall, this work highlights the complexity of HDAC6's contribution to immune regulation and suggests that while high selectivity may reduce toxicity, it could limit therapeutic efficacy in immuno-oncology contexts."

Immunomodulating • IO biomarker • Hematological Malignancies • Oncology • Solid Tumor • CRBN • IFNG • IL10 • IL17A • IL1B • PD-L1 • TNFA

Inhibiting both Class IIb HDACs is superior to isoform-specific inhibition for improved antitumor immune response. (AACR 2026) - "It is reported that HDAC6 inhibitors, Tubastatin A and Nexturastat A (NextA), inhibit both HDAC6 and HDAC10 isoforms with varying selectivity...In this study, we report novel HDAC inhibitors, ITF3756 and ITF6475, referred to as ITF3 and ITF6, respectively, and their effects on macrophage function and phenotype using murine bone marrow-derived Mφs (BMDMs), murine RAW264.7 cells, human PBMC-isolated monocyte-derived Mφs, and Thp1 monocyte-derived human Mφs...Finally, a combination of ITF3 with radiation therapy significantly suppressed Myc-Cap prostate cancer tumor growth while inducing an immune-stimulatory effect, as evidenced by increased infiltration of antitumor M1 Mφs and CD8 effector T cells. Overall, we demonstrated that dual HDAC6/10 inhibition is superior to HDAC6 inhibition alone for instigating an immunomodulatory antitumor immune response in prostate cancer therapy."

Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • CD8 • GLI2 • HDAC10

Targeting lipogenesis promotes the synergistic effect of the selective HDAC6 inhibitor ITF3756 with bortezomib in colon cancer cells. (PubMed, Front Pharmacol) - "This hypothesis was confirmed by SREBP-1 silencing, which also potentiated the antitumor efficacy of the ITF3756/BTZ combination in HCT116 cells. Overall, these results reveal a particular antitumor efficacy of the selective HDAC6 inhibitor in combination with BTZ in colon cancer cells and suggest that inhibiting lipogenesis is a useful tool to further increase the synergistic effectiveness."

Journal • Colon Cancer • Colorectal Cancer • Metabolic Disorders • Oncology • Solid Tumor • ANXA5 • PPARG

HDAC6 inhibition by ITF3756 modulates PD-L1 expression and monocyte phenotype: insights for a promising immune checkpoint blockade co-treatment therapy. (PubMed, Front Immunol) - "These findings demonstrate that selective HDAC6 inhibition by ITF3756 modulates myeloid cell functionality by diminishing inhibitory signals and promoting T cell activation. Thus, ITF3756 represents a promising immunomodulatory agent that could enhance the efficacy of immune checkpoint blockade in cancer immunotherapy."

Checkpoint inhibition • IO biomarker • Journal • Colon Cancer • Colorectal Cancer • Oncology • Solid Tumor • CD40

Selective HDAC6 inhibitor ITF3756 induces IL-2 production and CD4 and NK cells activation in MLR assay (AACR 2025) - "Our data indicate that in a multicellular in vitro immune microenvironment, ITF3756 activates CD4 and NK cells and increases the production of IL-2. Given the importance of IL-2 in the tumor microenvironment, these new results, in addition to those previously collected on isolated myeloid and CD8 T cells, support the notion of the use of a HDAC6i such as ITF3756 for a promising immune checkpoint co-treatment therapy."

IO biomarker • Oncology • CD4 • CD8 • IL2 • IL2RA • IL7R • NKG2D

HDAC6 inhibition disrupts HDAC6-P300 interaction reshaping the cancer chromatin landscape. (PubMed, Clin Epigenetics) - "Our study highlights the substantial impact of HDAC6 inactivation on the chromatin landscape of cancer cells and suggests a role for P300 in contributing to the anticancer effects. The stabilization of P300 with HDAC6 inhibition proposes a potential shift in therapeutic focus from HDAC6 itself to its interaction with P300. This finding opens new avenues for developing targeted cancer therapies, improving our understanding of epigenetic mechanisms in cancer cells."

Journal • Oncology • Targeted Protein Degradation

ITF3756 increases NKG2D expression and cytotoxic activity of activated human CD8 T cells (AACR 2024) - "ITF3756 increased the expression of NKG2D and this could be a driver of the increased cytolytic activity. One mechanism of tumor immune escape is the downregulation of MHC I. Our results suggest that ITF3756 could be used to improve the efficacy of T cell therapy by enhancing the cytolytic activity even in the absence of MHC I."

IO biomarker • Oncology • CD8 • GZMB • IFNG • NKG2D

HDAC6 inhibition reshapes the epigenome of cancer via P300 stabilization (AACR 2024) - "This aim includes an examination of the stabilization of the lysine acetyltransferase P300 and its implications for chromatin structure and function.Methods & In this study, ITF3756 and CRISPR/Cas9 were employed to inactivate HDAC6 across a variety of cancer cell lines (Jurkat, MDA 231, HCC1806, 4T1, and B16F10 melanoma)... This research shows that the chemical or genetic inactivation of HDAC6 impacts cancer cell proliferation and chromatin architecture, underscoring the potential of HDAC6 as a target in cancer therapeutics.. A critical finding of this study is the stabilization of P300, which offers new perspectives on HDAC6's functionality and its role as an epigenetic modifier in cancer cells."

Melanoma • Oncology • Solid Tumor • AKT1 • CASP7 • GAS6 • ITGB3 • NF1 • SOX9 • TGFB2

Selective HDAC6 inhibition by ITF3756 modifies the landscape of gene and protein expression in human monocytes: Possible identification of a specific biomarker signature (AACR 2023) - "Surface protein expression of M2 macrophages biomarkers in our panel, were determined by flow cytometry and all of them were significantly modulated in PBMCs. These data show how our approach successfully led both to the identification of a biomarker signature that could be used in clinical trials to monitor the pharmacodynamic effect of ITF3756, and to the discovery of previously unknown targets of HDAC6 inhibition."

Biomarker • IO biomarker • Hematological Malignancies • Oncology • ANXA6 • CD163 • CXCL3 • IRF6 • MRC1 • PD-L1