Deubiquitylating enzymes (DUBs) are promising therapeutical targets, especially in oncology (see my previous post dedicated to this topic). Today, I’d like to introduce you to new innovative substrates to screen selectively DUB inhibitors.
The anti-cancer property of the Vitamin K3 (Vitk3) was again recently studied by Dr Meng-Er Huang’s team (Curie Institute, CNRS UMR3348, Paris).
By using in vitro pro-oxydative cellular models, Dr Huang and collaborators observed a cancer-selective cytotoxicity of vitk3 in Peroxyredoxin 1 (PRDX1 aka PRX1)-deficient cancer cell lines.
To further investigate the underlying molecular mechanisms, the authors used a stably PRX1-depleted HeLa cell line (PRX1-) (vs. Control (PRX1+)) under various experimental conditions. They notably treated PRX1- and PRX1+ cell lines by vitk3 and 6 other known anticancer molecules targeting different cellular events (microtubule (vinblastine & taxol); DNA (doxorubicin & daunorubicin); DNA transcription (actinomycin D) and cell cycle (5-FU)). [Read more…]
Montelukast is a marketed drug used for asthma treatment and to relieve symptoms of seasonal allergies. It is known to function as a leukotriene receptor antagonist.
In a recent study in which young and old rats were treated with Montelukast, Maschallinger et al. (1) could show that the drug reduces neuroinflammation, elevates hippocampal neurogenesis and improves learning and memory in old animals. They could further demonstrate that some of these findings are mediated through an inhibitory effect on the GPR17 receptor.
GPR17 is an orphan G-protein-coupled receptor that is abundant in the CNS, and has been shown to play a key role in regulating oligodendrocyte differentiation and maturation although little has been known about the exact mechanism through which GPR17 influences myelination (2).
The most important result of their study is that cognitive function of old animals could be restored by the treatment with Montelukast. This could be shown in two different behavioral tests. While young rats have not been affected by the drug treatment, Montelukast significantly improved task learning in 20-month old rats. Non-cognitive behaviours such as anxiety-like behaviour, depression-like symptoms, exploration and locomotion as well as changes in body weight have not been affected by Montelukast treatment. Furthermore the authors found that Montelukast reduced microglia reactivity and restored hippocampal neurogenesis in old rats.
These findings might open the door for new potential pharmaceutic applications for Montelukast in treating dementia.
Modulators of GPR17
Focus Biomolecules recently released Montelukast to facilitate GPR17 related research activities. Focus Biomolecules also offer 2 more GPR17 modulators through tebu-bio.
- Montelukast: Leukotriene antagonist and GPR17 ligand
- MDL29,951: MDL29,951 is a new, highly specific, small molecule activator of GPR171 that has been shown to be active in intact cells1. The ability to specifically activate GPR17 allows for the study of the exact role GPR17 plays in the maturation of
oligodendrocytes and facilitates further study of this important process.
- Pranlukast: GPR17 antagonist and CysLT1 antagonist.
Interested in these modulators? Please contact us with the form below
(1) J. Maschallinger et al., Structural and functional rejuvenation of the aged brain by an approved anti-asthmatic drug, Nat Commun. 6, 8466 (2015)
(2) S. Hennen et al.,Decoding signaling and function of the orphan G protein-coupled receptor GPR17 with a small-molecule agonist, Sci Signal. 6, 298 (2013)
Microbial metabolites are a source of unequalled elements for in vitro assays. Sometimes neglected, these active molecules naturally provide a large spectrum of structural diversity for Drug discovery and antibiotics development programs. In this post, 6 metabolites and their respective properties are highlighted with the hope of refreshing our minds, a little bit, of the importance of such molecules in innovative research discovery.
While it is likely that all Ubiquitin-Like proteins (UBLs) will be important for drug discovery because of these associations, Ubiquitin has been the most completely validated for this purpose by genetic, biological, and biochemical evidence. The enzymes of the Ubiquitin pathway are emerging as pioneer drug targets for many therapeutic areas.
The ubiquitin family of proteins is an important means of regulating protein trafficking, cell division, apoptosis, and metabolism in cells. Turnover of most cellular proteins is effected by ubiquitin tagging, which marks them for transport to the 26S proteasome for degradation. [Read more…]
In a recent post, I concentrated on the role of HDACs in cancer: Histone Deacetylases (HDACs) and Cancer and mentioned that some HDACs are overexpressed and show very high activities in a number of tumours. Today, I ‘ll focus on the role of HDACs in Alzheimer’s disease, which accounts for 60 to 70% of dementia cases. Taking into account the demographic development – it has been projected that by 2050, people aged 60 and over will account for 22% of the world’s population – and the fact that it affects approx. 6% of people older than 65 years, the WHO stated that “Alzheimer disease (AD) has become a major public health concern…” (Background Paper 6.11; 2013). [Read more…]
Histone Methyltransferases (ex. EZH1 and EZH2, and G9a) and their counter-parts (Histone demethylases like JARID1, the KDM4, and the JMJD family) have become promising targets for inhibitor screenings, especially in Cancer drug discovery. (1, 2) Accessing a wide variety of pure and well-characterized bioactive small molecules is of importance when characterizing these enzymes.
Here, we’ve compiled a list of 19 bioactive compounds currently seen in the literature when studying Histone Methyltransferases and Demethylases in Drug Discovery. [Read more…]
The treatment of diseases by inducing, enhancing, or surpressing an immune response is referred to as Immunotherapy. T-cell activation and inactivation requires the coordination of various co-inhibitory and co-stimulatory signals and most immunotherapies modulate these signals.
Therapeutic manipulation of immunopathways has lead to promising clinical results for the treatment of a number of diseases such as cancer, autoimmune diseases and inflammatory diseases. Research in this field is rapidly evolving as scientists seek to identify the next generation of therapies.
Over the past 12 months I have introduced a number of pathways and proteins involved, which represent potential targets for drug discovery campaigns and I’ve presented assays to measure inhibitor effects on these pathways (B7-1 / CD28 and B7-1 / CTLA4; PD-1/PD-L1/PD-L2; BLTA:HVEM, CD47:SIRPα; GITR:GITRL; CD40:CD40L; CD137:CD137L; IDO).
Which roles do IDO and TDO play in Immunotherapy? Immune evasion is one of the identifying hallmarks of cancer and researchers are investigating the complex mechanisms that enable cancer cells to evade the host’s immune system. In the context of a tumor, Tryptophan (Trp or L-Trp) catabolizing enzymes have been shown to assist cancer cells in immune evasion. [Read more…]
Histon Deactetylases (HDACs) are overexpressed and show very high activities in a number of tumor cells. Expression of HDAC1, -5, and -7 can be even used as a cancer biomarker. Moreover, they play a crucial role in oncogene expression.
HDACs remove acetyl groups from N acetyl lysine residues in histones. These enzymes belong to a number of enzymes which control the condensation status of nucleosomes (structure of a mono nucleosome is shown in Fig.1). While acetylation of histones by Histone acetyltransferases leads to decondensation and thus allows DNA binding proteins to interact with exposed sites to activate gene transcription, the activity of HDACs allows histones to wrap the DNA more tightly.