Histone deacetylase inhibitors represent the most important class of drugs for the treatment of human cancer and other diseases due to their influence on cell growth, differentiation, and apoptosis. Among the well-known eighteen histone deacetylases, histone deacetylase 6 (HDAC6), which is involved in oncogenesis, cell survival, and cancer cell metastasis, is of great importance. Using the CDK and alvaDesc molecular descriptors and the Random Forest and EXtreme Gradient Boosting methods, we propose a number of adequate QSAR classification models, which are integrated into a consensus model and are freely available on the OCHEM web platform (https://ochem.eu). The consensus QSAR model is used for virtual screening of a series of seven new compounds, the derivatives of N-((hydroxyamino)-oxoalkyl)-2-(quinazoline-4-ilamino)-benzamides, the synthesis schemes of which are also presented in this work. In vitro evaluation of the inhibitory activity (IC₅₀) of this series of compounds against HDAC6 allowed us to confirm the results of virtual screening and to reveal promising compounds V-2 and V-4, IC₅₀ of which is 3.25 nM and 0.04 nM, respectively. The subsequent in silico evaluation of the main ADMET properties of active compounds V-2 and V-4 allowed us to find that they have acceptable pharmacokinetic parameters and level of acute toxicity.

Introduction. Early malignant tumor detection programs have significantly increased the survival rate of breast cancer patients but the results of drug therapy for this pathology are not always highly effective. Recently discovered iron-dependent cell death, ferroptosis, makes it a promising therapeutic target to reduce the recurrence rates.Objective – to study the induction of ferroptosis in breast cancer cells MCF-7 by quinazoline derivatives synthesized at the Research Institute of Experimental Diagnostics and Therapy of Tumors of the N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia and to evaluate its antitumor activity on transplanted breast carcinoma Ca-755.Materials and methods. Derivatives of 3-hydroxyquinazoline were obtained by chemical synthesis and have a purity of at least 95 %. In this study 2D cultivation of MCF7 cells, phase-contrast and fluorescence microscopy, and a model of experimental growth of breast carcinoma Ca-755 in female hybrids of immunocompetent mice F1 (C57Bl/6 × DBA/2) were used.Results. Five derivatives of 3-hydroxyquinazoline, analogues of erastine, were studied in this work. The ferroptotic cell death was identified by the level of lipid peroxidation at the concentrations of 1/3 and 1/5 IC50. The level of lipid peroxidation induced by compound 3 was comparable with the activity of erastin in MCF7 cells at both 1/3 and 1/5 of IC50, the activity of the other four quinazoline derivatives was 50–70 % of the activity of erastin. In in vivo experiments at a dose of 30 mg/kg the antitumor efficacy of the compound 3 was higher than that of erastin at the same dose.Conclusion. The data obtained suggest that quinazoline derivative 3 might be considered as a promissisng antitumor agent to treat breast cancer.

Introduction. The main cause of clinical progression of tumor under the conditions of treatment is the resistance. Reactivate apoptosis in resistant to chemotherapy cells is impossible, the tumor grows into an irreversible growth phase. Recently published data on the ability of ferroptosis inducers to induce the death of resistant cells opens up new possibilities for improving the effectiveness of antitumor therapy.The purpose of the study – assessment of the mechanism of ferroptosis induction of the synthesized analogue of erastin OVN‑002 on Mel Z melanoma cells and investigation of its antitumor activity on transplanatated B‑16 melanoma of mice.Materials and methods. In this study 2D cultivation of metastatic Mel Z melanoma cells, phase‑contrast and fluorescence microscopy, and a model of experimental growth of B‑16 melanoma in female hybrids of immu‑ nocompetent mice F1 (C57Bl/6 × DBA / 2) were used. The antitumor effect was evaluated by measurement of tumor growth inhibition (TGI, %) and increase of life span of the treated animals as compared to the control ones.Results. The cytotoxic activity of OVN‑002 was equal to the activity of erastin on metastatic melanoma cells Mel Z: 744 ± 20 and 719 ± 20 a. u., respectively. OVN‑002 at a dose 50 mg / kg reduced the growth of experimental melanoma B‑16 about 81 % (TGI 81–57 %, p 0.05). The effect was stable up to 7th day, while erastin showed only a direct antitumor effect (TGI 65 %, p 0.05).Conclusion. The data obtained suggest that OVN‑002 might be considered as a novel antitumor agent.

The HDAC6 (histone deacetylase 6) enzyme plays a key role in many biological processes, including cell division, apoptosis, and immune response. To date, HDAC6 inhibitors are being developed as effective drugs for the treatment of various diseases. In this work, adequate QSAR models of HDAC6 inhibitors are proposed. They are integrated into the developed application HDAC6 Detector, which is freely available at . The web application HDAC6 Detector can be used to perform virtual screening of HDAC6 inhibitors by dividing the compounds into active and inactive ones relative to the reference vorinostat compound (IC50 = 10.4 nM). The web application implements a structural interpretation of the developed QSAR models. In addition, the application can evaluate the compliance of a compound with Lipinski's rule. The developed models are used for virtual screening of a series of 12 new hydroxamic acids, namely, the derivatives of 3-hydroxyquinazoline-4(3H)-ones and 2-aryl-2,3-dihydroquinazoline-4(1H)-ones. In vitro evaluation of the inhibitory activity of this series of compounds against HDAC6 allowed us to confirm the results of virtual screening and to select promising compounds V-6 and V-11, the IC50 of which is 0.99 and 0.81 nM, respectively.