Histone deacetylases (HDACs) are the major regulators of the balance of acetylation of histone and non-histone proteins. In contrast to other HDAC isoforms, HDAC6 is mainly involved in maintaining the acetylation balance of many non-histone proteins. Therefore, the overexpression of HDAC6 is associated with tumorigenesis, invasion, migration, survival, apoptosis and growth of various malignancies. As a result, HDAC6 is considered a promising target for cancer treatment. However, none of selective HDAC6 inhibitors are in clinical use, mainly because of the low efficacy and high concentrations used to show anticancer properties, which may lead to off-target effects. Therefore, HDAC6 inhibitors with dual-target capabilities represent a new trend in cancer treatment, aiming to overcome the above problems. In this review, we summarize the advances in tumor treatment with dual-target HDAC6 inhibitors.

Dopamine is an important neurotransmitter in the human brain and its altered concentrations can lead to various neurological diseases. We studied the binding of novel compounds at the dopamine D₂ (D₂R) and D₃ (D₃R) receptor subtypes, which belong to the D₂‐like receptor family. The synthesis, in silico, and in vitro characterization of 10 dopamine receptor ligands were performed. Novel ligands were docked into the D₂R and D₃R crystal structures to examine the precise binding mode. A quantum mechanics/molecular mechanics study was performed to gain insights into the nature of the intermolecular interactions between the newly introduced pentafluorosulfanyl (SF₅) moiety and D₂R and D₃R. A radioligand displacement assay determined that all of the ligands showed moderate‐to‐low nanomolar affinities at D₂R and D₃R, with a slight preference for D₃R, which was confirmed in the in silico studies. N‐{4‐[4‐(2‐Methoxyphenyl)piperazin‐1‐yl]butyl}‐4‐(pentafluoro‐λ6‐sulfanyl)benzamide (7i) showed the highest D₃R affinity and selectivity (pK_i values of 7.14 [D₂R] and 8.42 [D₃R]).

Background/Objectives: Alterations in the actin cytoskeleton correlates to tumor progression and affect critical cellular processes such as adhesion, migration and invasion. Rho-associated coiled-coil-containing protein kinases (ROCK1 and ROCK2), important regulators of the actin cytoskeleton, are frequently overexpressed in various malignancies. The aim of this study was therefore to identify the key structural features of ROCK1/ROCK2 inhibitors using computer-aided drug design (CADD) approaches. In addition, new developed ROCK inhibitors provided a significant framework for the development of multitarget therapeutics—ROCK/HDAC (histone deacetylases) multitarget inhibitors. Methods: 3D-QSAR (Quantitative structure-activity relationship study) and molecular docking study were employed in order to identify key structural features that positively correlate with ROCK inhibition. MDA-MB-231, HCC1937, Panc-1 and Mia PaCa-2 cells were used for evaluation of anticancer properties of synthesized compounds. Results: C-19 showed potent anti-cancer properties, especially enhancement of apoptosis and cell cycle modulation in pancreatic cancer cell lines. In addition, C-19 and C-22 showed potent anti-migratory and anti-invasive effects comparable to the well-known ROCK inhibitor fasudil. Conclusions: In light of the results of this study, we propose a novel multi-target approach focusing on developing dual HDAC/ROCK inhibitors based on the structure of both C-19 and C-22, exploiting the synergistic potential of these two signaling pathways to improve therapeutic efficacy in metastatic tumors. Our results emphasize the potential of multi-target ROCK inhibitors as a basis for future cancer therapies.

Xanthene derivatives have become a group of molecules of great importance in discovering of new anticancer drugs. Recent studies of our group performed on xanthen-3-one and xanthen-1,8-dione derivatives have shown their antiproliferative activity on HeLa cervical cell lines. Obtained IC₅₀ values together with calculated molecular descriptors were subjected to Quantitative Structure-Activity Relationship (QSAR) study in order to identify the most relevant molecular features responsible for the observed antiproliferative activity of compounds. Partial Least Square statistical method and the same training and test set were used to obtained statistical parameters for internal and external validation in 2D- and 3D- QSAR study. The obtained QSAR models have shown next results: 2D-QSAR: R²=0.741, Q²=0.792, R²_pred=0.875 and 3D-QSAR: R²=0.83, Q²=0.951, R²_pred=0.769. Based on the performed QSAR analysis and calculated ADMET properties, novel xanthene derivatives with enhanced antiproliferative activity were designed.

Human papillomaviruses (HPV) are the most common sexually transmitted pathogens worldwide, leading to infections with a wide range of clinical manifestations: from benign conditions to different types of cancer in women and men as well. Cervical cancer is highly correlated with persistent high-risk-HPV (HR-HPV) infection, which is the key factor in emergence of 99.99% of cervical cancer cases. The most effective way to prevent HPV-related cancers is vaccination. There are three available prophylactic HPV vaccines: bivalent, quadrivalent and nonavalent. The nonavalent vaccine is gradually replacing other HPV vaccines in most countries and can be given from year 9, but it is commonly routinely implemented at the age of 11 to 12. The World Health Organization has recognised cervical cancer as a global threat and has announced the so-called 90-70-90 strategy to reduce and even eliminate cervical cancer. This strategy implies that 90% of girls should be vaccinated by the age of 15, 70% of women should be screened for cervical cancer, and 90% of women diagnosed with cervical disease should receive adequate treatment. Although different treatment options are available: surgery, radiation therapy, chemotherapy, and advanced target therapy using monoclonal antibodies, great efforts are needed to achieve the goals set by the World Health Organization to eliminate cervical cancer.