SETDB1 as a cancer target: challenges and perspectives in drug design.

Genome stability is governed by chromatin structural dynamics, which modify DNA accessibility under the influence of intra- and inter-nucleosomal contacts, histone post-translational modifications (PTMs) and variations, besides the activity of ATP-dependent chromatin remodelers. These are the main ways by which chromatin dynamics are regulated and connected to nuclear processes, which when dysregulated can frequently be associated with most malignancies. Recently, functional crosstalk between histone modifications and chromatin remodeling has emerged as a critical regulatory method of transcriptional regulation during cell destiny choice. Therefore, improving therapeutic outcomes for patients by focusing on epigenetic targets dysregulated in malignancies should help prevent cancer cells from developing resistance to anticancer treatments. For this reason, SET domain bifurcated histone lysine methyltransferase 1 (SETDB1) has gained a lot of attention recently as a cancer target. SETDB1 is a histone lysine methyltransferase that plays an important role in marking euchromatic and heterochromatic regions. Hence, it promotes the silencing of tumor suppressor genes and contributes to carcinogenesis. Some studies revealed that SETDB1 was overexpressed in various human cancer types, which enhanced tumor growth and metastasis. Thus, SETDB1 appears to be an attractive epigenetic target for new cancer treatments. In this review, we have discussed the effects of its overexpression on the progression of tumors and the development of inhibitor drugs that specifically target this enzyme.

Human sirtuin 2 inhibitors, their mechanisms and binding modes.

The silent information regulator (sirtuin) is a family of enzymes involved in epigenetic processes with lysine deacetylase activity, having as substrates histones and other proteins. They participate in a wide range of cellular and pathologic processes, such as gene expression, cell division and motility, oxidative-induced stress management, metabolic control and carcinogenesis, among others, thus presenting as interesting therapeutic targets. In this article, the authors describe the inhibitory mechanisms and binding modes of the human sirtuin 2 (hSIRT2) inhibitors, which had their complexes with the enzyme structurally characterized. The results help pave the way for the rational designing of new hSIRT2 inhibitors and the development of novel therapeutic agents targeting this epigenetic enzyme.

Aporphine and isoquinoline derivatives block glioblastoma cell stemness and enhance temozolomide cytotoxicity.

Glioblastoma (GBM) is the most aggressive and common primary malignant brain tumor with limited available therapeutic approaches. Despite improvements in therapeutic options for GBM patients, efforts to develop new successful strategies remain as major unmet medical needs. Based on the cytotoxic properties of aporphine compounds, we evaluated the biological effect of 12 compounds obtained through total synthesis of ( ±)-apomorphine hydrochloride (APO) against GBM cells. The compounds 2,2,2-trifluoro-1-(1-methylene-3,4-dihydroisoquinolin-2(1H)-yl)ethenone (A5) and ( ±)-1-(10,11-dimethoxy-6a,7-dihydro-4H-dibenzo[de,g]quinolin-6(5H)-yl)ethenone (C1) reduced the viability of GBM cells, with 50% inhibitory concentration ranging from 18 to 48 µM in patient-derived GBM cultures. Our data show that APO, A5 or C1 modulate the expression of DNA damage and apoptotic markers, impair 3D-gliomasphere growth and reduce the expression of stemness markers. Potential activity and protein targets of A5, C1 or APO were predicted in silico based on PASS and SEA software. Dopamine receptors (DRD1 and 5), CYP2B6, CYP2C9 and ABCB1, whose transcripts were differentially expressed in the GBM cells, were among the potential A5 or C1 target proteins. Docking analyses (HQSAR and 3D-QSAR) were performed to characterize possible interactions of ABCB1 and CYP2C9 with the compounds. Notably, A5 or C1 treatment, but not temozolomide (TMZ), reduced significantly the levels of extracellular ATP, suggesting ABCB1 negative regulation, which was correlated with stronger cytotoxicity induced by the combination of TMZ with A5 or C1 on GBM cells. Hence, our data reveal a potential therapeutic application of A5 and C1 as cytotoxic agents against GBM cells and predicted molecular networks that can be further exploited to characterize the pharmacological effects of these isoquinoline-containing substances.