domatinostat (4SC-202)

Innovative treatments are being explored, including combination therapies such as metformin with 4SC-202, which show promise in reducing tumor cell migration and enhancing chemotherapy sensitivity. Additionally, nanoengineered formulations of cisplatin aim to improve drug delivery specificity and minimize systemic toxicity, offering a more patient-friendly approach...Addressing these areas is crucial for advancing prevention, enabling early diagnosis, and improving survival and quality of life for patients with OCSCC. This work supports ongoing progress in oral cancer research and clinical care.

Among the compounds, domatinostat and entinostat exhibited the strongest affinities (ΔGbind ≈ -70 kcal/mol), in reasonable agreement with experimental data (r = 0.60). This supports an allosteric inhibition mechanism in which ligands lock HDAC3 into inactive conformations. Collectively, these findings offer mechanistic insights into HDAC3 regulation and highlight structural hot spots for the rational design of selective inhibitors with potential applications in targeted breast cancer therapy.

Simultaneous inhibition of the class I HDACs, HDAC1 and HDAC2, reduced FOXM1 expression and suppressed cell proliferation in high-grade meningiomas. Furthermore, the class I HDAC inhibitor domatinostat inhibited FOXM1 expression and cell proliferation in high-grade meningioma cells within a concentration range that was not toxic to normal cell lines. These results suggest the potential of domatinostat as a therapeutic option for the treatment of high-grade meningiomas, which are often difficult to manage clinically.

Together, the results suggest that the unique ability of domatinostat to activate the p53-dependent and -independent programs of BAX expression selectively in GSCs could account for its preferential cytotoxicity against GSCs. Our findings may also help guide the selection of patients with glioblastoma, and possibly those with other types of cancer, who are most likely to benefit from domatinostat treatment and optimize the treatment strategy for such patients.

P1/2, N=44, Completed, The Netherlands Cancer Institute | Active, not recruiting --> Completed

Compound 20c effectively modulated the expression of biomarkers associated with LSD1 and HDAC inhibition and demonstrated superior antiproliferative activity compared to SAHA and 4SC-202 across multiple colorectal cancer cell lines...It demonstrated significantly enhanced antitumor efficacy compared to SAHA, without causing observable toxicity. These findings highlight the potential of LSD1/HDAC dual inhibitors for the treatment of malignant cancers.

To address the question of whether the IFNg can be analyzed using primary tumor material (P-IFNg) instead of LN-IFNg or, in the case of incongruencies, has a higher predictive value when combined with LN-IFNg, we analyzed the IFNg signature in paired samples (P and LN) from stage III melanoma pts. Paraffin primary tumor tissue from pts with stage III melanoma, treated in the OpACIN-neo, PRADO and DONIMI trials (neoadjuvant anti-PD1 +/- anti-CTLA4 +/- domatinostat), was retrospectively analyzed with the nanostring nCounter PanCancer immune profiling panel and compared to fresh frozen LN biopsies. Our results suggest that pts with concurrently high IFNg-signature expressions (high IFNg in P and LN) have a better outcome than LN-IFNg high pts only. If confirmed, these findings could inform treatment selection and prognosis.

P2, N=19, Completed, 4SC AG | Active, not recruiting --> Completed | Trial completion date: Dec 2024 --> Feb 2024

P1/2, N=44, Active, not recruiting, The Netherlands Cancer Institute

P1/2, N=44, Active, not recruiting, The Netherlands Cancer Institute | Phase classification: P1b --> P1/2

Preliminary drug screening data suggests that HDAC inhibitors, such as Domatinostat, have the potential to specifically target the MCs in order to inhibit metastasis in UPS... HDACs have been identified as potential therapeutic targets for metastatic UPS. Previous data has shown that a single subpopulation of cells is responsible for the formation of these distant lesions. Ongoing studies aim to identify which HDACs are important for metastasis in addition to elucidating their mechanism of disease progression and further analysis of the effect of pharmacological inhibition.

Cell viability, as well as protein and mRNA expression of FOXM1 and its transcriptional target survivin, was examined after domatinostat treatment of TOV21G and SKOV3 ovarian cancer cell lines in the absence or presence of cisplatin and paclitaxel. Survivin inhibition was sufficient to reduce the viability of ovarian cancer cells alone and in combination with the chemotherapeutic agents. Our findings suggest that domatinostat, which effectively targets the FOXM1-survivin axis required for the viability of ovarian cancer cells, is a promising option for the treatment of ovarian cancer.