Duvyzat (givinostat)

P2, N=90, Active, not recruiting, Italfarmaco | Trial completion date: Dec 2025 --> Dec 2026 | Trial primary completion date: Jun 2025 --> Dec 2026

P3, N=220, Recruiting, Italfarmaco | Not yet recruiting --> Recruiting

P3, N=138, Recruiting, Italfarmaco | Not yet recruiting --> Recruiting

Herein, we engineered 5-Aza (a DNA methyltransferase inhibitor) and ITF-2357 (a histone deacetylase inhibitor) into a tungsten-based nano-radiosensitizer (PWAI), to suppress MYC rising and awaken robust radiotherapeutic antitumor immunity...Unlike the radiation treatment alone, PWAI-triggered immuno-radiotherapy remarkably enhances anti-tumor immune responses involving the tumor antigen presentation by dendritic cells, and improves intratumoral recruitment of cytotoxic T lymphocytes and their memory-phenotype formation in 4T1 tumor-bearing mice. Downgrading the radiotherapy-induced MYC overexpression via the dual-epigenetic reprogramming strategy may elicit a robust immuno-radiotherapy.

In silico molecular docking study further revealed that out of 34 compounds, the flavonoid Andrographidine E had the highest binding affinities towards HDAC1 (-9.261 Kcal mol) and 3 (-9.554 Kcal mol) when compared with the control drug Givinostat (-8.789 and -9.448 Kcal mol)...Most of them showed high or comparable inhibitory potentials towards HDAC target protein. Finally, the stability of top-ranked complexes (Andrographidine E-HDAC1 and HDAC3; Andrographiside-HDAC8) at the physiological condition was validated by Molecular Dynamic Simulation and MM-PBSA study.Communicated by Ramaswamy H. Sarma.

P2/3, N=206, Enrolling by invitation, Italfarmaco | Trial completion date: Dec 2023 --> Dec 2025 | Trial primary completion date: Dec 2023 --> Dec 2025

P3, N=220, Not yet recruiting, Italfarmaco

This study shows that lncH19 expression contributes to ITF2357-induced apoptosis by stabilizing TP53. Overall, we suggest that lncH19 expression may be exploited to favor HDACi-induced cell death and overcome 5-fluorouracil chemoresistance.

In the PDA organoid-based screen, epigenetic inhibitors ITF2357 and I-BET151 are identified, which in combination with anti-PD-1 based therapy show considerably greater anti-tumor effect. The combinatorial treatment turns the TME from immunosuppressive to immunoactive, up-regulates the MHC-I antigen processing and presentation, and enhances the effector T cell activity. The standardized PDA organoid model has shown great promise to accelerate drug discovery for the immunosuppressive cancer.

ITF2357 also targeted BRAF in A375 cells but not wild-type p53, which increased, most likely favouring apoptosis. Silencing experiments confirmed that the response to ITF2357 in BRAF-mutated cells depends on p53 status, thus providing a rationale for melanoma-targeted therapy.

These consist of the Bcl-2 inhibitor ABT-199 (Venetoclax), the HSP90 inhibitors AUY922 (Luminespib), EC144, PF-04929113, NVP-HSP990, the BET bromodomain inhibitor JQ1, the microtubule polymer stabilizer Paclitaxel, as well as two agents of the classical chemotherapy for BCP-ALL, the glucocorticoid Dexamethasone and the antimitotic Vincristine...In the combination setting, we managed to couple Givinostat, our previously established compound active for CRLF2r ALL cases, with Trametinib (ZIP synergy 7.04 and 16.83 for MUTZ-5 and MHH-CALL-4 respectively) or Venetoclax (ZIP synergy 9.23 and 5.03), thus providing a successful synergistic targeting further confirmed in CRLF2r ALL blasts, whose synergistic mechanism of action is currently investigated. This study has highlighted the emerging benefit of HTP drug screening applications guiding the early design oftherapies for multiple or specific patient subgroups in an approach of repurposing drugs available in the pharmacological landscape. Drug sensitivity, Targeted therapy, B cell acute lymphoblastic leukemia, Down Syndrome

We isolated T cells from the spleens of healthy C57/Bl6 mice and treated the cells with a DNMTi, 5-azacytidine (Aza) at 500 nmol/L, and an HDACi, ITF-2357 (ITF) at 100 nmol/L, singly and in combination. These changes were evident at the transcript and secreted cytokine level, pointing to transcriptional upregulation of the target genes. This study demonstrates direct activation of T cells by DNMTis and HDACis and provides mechanistic insight into the role of epigenetic therapies in the murine model of OC.

Givinostat, in addition to its own cytotoxic activity, sensitizes GSCs to temozolomide by inhibiting Sp1-dependent MGMT expression in GSCs. Combining givinostat with temozolomide could therefore be a rational therapeutic strategy to effectively eliminate GSCs and thus help overcome the therapy resistance of GBM.

Taken together, HDAC inhibitor ITF2357 restores miR-130a-3p expression by inhibiting HDAC2, thereby repressing Rad51 and ultimately diminishing resistance of mut-KRAS NSCLC to Pem. Our findings suggested HDAC inhibitor ITF2357 as a promising adjuvant strategy to enhance the sensitivity of mut-KRAS NSCLC to Pem.

Here, we focus on the effects of the pan-HDAC inhibitor ITF2357 (Givinostat) in comparison with SAHA (Vorinostat) in melanoma cells bearing BRAF V600E oncogenic mutation. ITF2357 stimulated an early pro-survival autophagic response, which was followed by apoptosis, as indicated by apoptotic markers evaluation and the protective effects exerted by the pan-caspase inhibitor z-VADfmk. Overall, our data indicate for the first time that ITF2357 targets oncogenic BRAF in melanoma cells and induces a switch from autophagy to classic apoptosis, thus representing a possible candidate in melanoma targeted therapy.

Further analyses revealed that givinostat and dacinostat were the two most potent HDAC inhibitors that restored CTL sensitivity in SW1990 and BxPC3 CTL-resistant cells. Through our in silico and in vitro studies, we demonstrate the novel role of HDAC inhibition in restoring CTL resistance and that combinations of HDACi with CTL may represent a promising therapeutic strategy, warranting its further detailed molecular mechanistic studies and animal studies before embarking on the clinical evaluation of these novel combined PDAC treatments.

ITF-2357 was the most significant compound with an IC50 lower than 0.1 uM...As PDX retain the principal histologic and genetic characteristics of the primary tumors, mad it a valuable research tool in predictive clinical efficacy. In this study, we first established a malignant GCTB PDX model, which might further accelerate the progress of drug development in malignant GCTB.

Expression of Ik-6 could be suppressed by treatment with the pro-apoptotic type II histone deacetylase inhibitor givinostat. In 17 adult ALL samples, we noted the Ik-6 isoforms in 6 of 15 BCR-ABL1, and 1 of 2 BCR-ABL1 cases, with Ik-8 also expressed in one case. Cases with Ik-6 expression showed inferior survival as well as older age at presentation, lower expression of CD10 and more commonly a diploid karyotype.

Current treatments include aspirin, phlebotomy, and cytoreductive drugs (most commonly hydroxyurea). This would completely change the current therapeutic paradigm and guidelines for PV management. Although surrogate clinical study endpoints may suffice for regulatory purposes, thrombosis reduction and prevention of disease progression remain most important to patients and clinicians.

Several compounds of these structural classes have been approved for clinical uses to treat different types of cancer, such as givinostat (ITF2357) and belinostat (PXD-101)...Two new series of N-hydroxybenzamides and N-hydroxypropenamides analogues (4a-j, 6a-j) designed based on the structural features of nexturastat A, AR-42, and PXD-101, were synthesized and evaluated for HDAC inhibitory potency as well as cytotoxicity against three human cancer cell lines (SW620 (colorectal adenocarcinoma), PC3 (prostate adenocarcinoma), and NCI-H23 (adenocarcinoma, non-small cell lung cancer)...Various compounds, e.g. 6a-e, especially compound 6e, were up to 5-fold more potent than suberanilohydroxamic acid (SAHA) in terms of cytotoxicity...These compounds also comparably inhibited HDACs with IC50 values in sub-micromolar range. Docking experiments showed that these compounds bound to HDAC2 at the enzyme active binding site with the same binding mode of SAHA, but with higher binding affinities.