Drug Discovery

Find the best epigenetic enzyme substrate for your needs

20/04/2016 By Ali El Baya, PhD Leave a Comment

Fig. 1: Nucleosome structure

Nucleosomes are basis units of DNA packaging in eukaryotic cells. A core particle (mono-nucleosome) consists of a segment of DNA called core DNA (147 bp in length) wound around a histone octamer (Fig 1.). Histone octamers are made up of 2 copies of the the core histones H2A, H2B, H3, and H4. These mono-nucleosomes are connected by linker 80bp-long DNA. H1 histone, the so-called linker histone, binds to the linker DNA close to the entry and exit of the core DNA and is involved in chromatin compaction (Fig 1.). [Read more…]

CBR-5884 – a Serine biosynthesis inhibitor for cancer research

15/04/2016 By Ali El Baya, PhD Leave a Comment

Metabolic pathways are upregulated in cancer cells to promote their growth and proliferation. The evidence pointing to the requirement of the amino acid serine in tumorigenesis is overwhelming. Serine is required for a large number of anabolic processes including amino acid and lipid biosynthesis. The enzyme 3-phosphoglycerate dehydrogenase (PHGDH) catalyzes the first committed step in cellular serine biosynthesis and is overexpressed in cancer cell lines and tumors.

CBR-5884 – a selective small molecule inhibitor of PHGDH recently discovered

CBR-5884 - focus biomolecules and tebu-bio

CBR-5884 chemical structure

Very recently, in a joint effort, the laboratories of Cantley, Lyssiotis and Lairson reported the discovery of a selective small molecule inhibitor of PHGDH designated CBR-5884 (1).

This compound inhibits serine biosynthesis in cancer cells and displays selective cytotoxicity to tumor cell lines overexpressing PHGDH. The identification of CBR-5884 as a drug-like inhibitor of serine biosynthesis is a breakthrough in targeting metabolism in cancer drug development. It is an important compound which provides proof of concept that PHGDH is a viable target, and may represent a lead molecule for the development of more potent analogs. In the mean time it serves as an important new tool compound for the study of cellular serine metabolism.

CBR-5884 is available as a research tool from Focus Biomolecules and tebu-bio

Focus Biomolecules has been the first company to make this promising compound available to the market for cancer research studies.

CBR-5884 (cat. nr 10-1588) can be purchased in Europe through tebu-bio. The compound is available in standard sizes (5 mg & 25 mg) or in bulk amounts (upon request).

Interested in testing CBR-5884 in your experimental setup ?

Please contact me through the form below!

Reference:

(1) Identification of a small molecule inhibitor of 3-phosphoglycerate dehydrogenase to target serine biosynthesis in cancers. E Mullarky et al. Proc. Acad. Natl. Sci. USA 2016 113:1778

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Cancer Immunotherapy: Generate your PD-L1 target cell line

06/04/2016 By Ali El Baya, PhD Leave a Comment

Fig 1: Immuno checkpoint proteins on T cell interact with ligands on APCs or cancer cells

In a recent post, I invited you to discover a cell line provided by BPS Bioscience over-expressing the checkpoint receptor PD-1. They have now just released a new kit which allows to generate a PD-L1 and TCR activator over-expressing target cell line. [Read more…]

Cancer immunotherapy: IDO1 inhibitors – reversible or irreversible?

17/03/2016 By Ali El Baya, PhD Leave a Comment

Fig 1: IDO and TDO – Tryptophan Catabolic Pathways

Trpytophan (trp) is an important and essential amino acid that has a variety of functions within the cell. In addition to being incorporated into the polypeptide chain of proteins, various catabolic pathways can produce a number of functional Trp derivatives. Trp is the biosynthetic precursor of the co-factor NAD, a number of antibiotics, and the neurotransmitters serotonin and melatonin.

The factors regulating the fate of Trp in the cell have yet to be fully elucidated, but likely involve specific enzymes that may vary in expression levels or with the cell type (Fig 1 – Shown is a depiction of two important tryptophan catabolic pathways and the enzymes that participate in the process). [Read more…]

Genetically encoded fluorescent biosensors for live cell discovery

08/03/2016 By Ali El Baya, PhD Leave a Comment

In drug discovery screening campaigns as well as in fundamental research activities, cellular parameters have to be measured and monitored in living cells regularly. Often fluorescent dyes are used to detect and follow some of the parameters. These methods are powerful, especially in screening large numbers of compounds, but have their limitations e.g. when it comes to measuring more than one parameter in the same living cell, or when specific locations in the cell shall be targeted.

To overcome these limitations and to provide tools to especially look into GPCR related signalling in the most comprehensive and detailed way currently possible, Montana Molecular have developed genetically encoded fluorescent biosensors to measure parameters such as cAMP, DAG, PIP2, Ca2+and voltage changes in living cells. [Read more…]

Cell signaling isn’t static… your cell culture shouldn’t be either

01/03/2016 By Jean-François Têtu, PhD Leave a Comment

Complex cell culture systems are emerging as key tools to improve physiological relevance of in vitro assay systems. There have been two main ways by which investigators attempt to improve mimicking of physiological conditions in cell and tissue culture. The first is to develop more complex model systems where two or more cell types are co-cultured in a 3D structure either separated by membranes or in spheroids [1]. The second is to incorporate fluidic-flow where the motion of the media itself has been shown to improve metabolic function and lifespan [2,3].

Despite the success of better recapitulating function at the cellular level using these two methods, neither of these approaches addresses the issue of the non-linear nature of the drug or toxicant exposure as is observed in an in vivo system [4]. As a result, the capacity to accurately predict in vivo pharmacokinetics and pharmacodynamics still falls short reaching at best 60-70% accuracy [5,6].

So what’s new in this area? We were interested to discover the following system, which we think will be of interest to many researchers. Let’s take a closer look at the characteristics and how it can be used. [Read more…]

Mutant PD-L1 proteins for antibody epitope mapping

16/02/2016 By Ali El Baya, PhD Leave a Comment

Cartoon of checkpoint proteins and ligands - BPS

Fig 1: Immune checkpoint proteins on T cells and their ligands on APCs and cancer cells

Knowledge about which epitopes are recognized by a blocking antibody can help researchers to develop improved antibodies for drug discovery and to better understand the mechanism of inhibition.

The binding of Programmed Cell Death Protein 1 (PD-1), one of the receptors expressed on activated T-cells (see Figure 1), to its ligands PD-L1 and PD-L2, negatively regulates immune responses. PD-1 ligands are found on most cancers, and PD-1:PD-L1/2 interaction inhibits T cell activity and allows cancer cells to escape immune surveillance.

The first therapeutic antibodies in this field have been directed against the checkpoint receptor PD-1 (Nivolumab by Bristol Myers Squibb and Pembrolizumab by Merck/MSD). The drugs have been approved for the treatment of diverse cancer types during the past years. The PD-1:PD-L1/2 pathway is also involved in regulating autoimmune responses, making these proteins promising therapeutic targets for a number of cancers, as well as multiple sclerosis, arthritis, lupus, and type I diabetes. Further research projects in this field are rapidly evolving as scientists seek to identify the next generation of therapies especially developing therapies combining different therapeutic approaches. [Read more…]

How to screen for inhibitors of PD-1 signalling in a cellular assay

09/02/2016 By Ali El Baya, PhD Leave a Comment

Fig 1: Immuno checkpoint proteins on T cell interact with ligands on APCs or cancer cells

The treatment of diseases by inducing, enhancing, or surpressing an immune response is referred to as Immunotherapy. Therapeutic manipulation of immunopathways has led to promising clinical results for the treatment of a number of diseases. The first therapeutic antibodies directed against the checkpoint receptor PD-1 have been already brought to the market (Nivolumab, Pembrolizumab) by Bristol Myers Squibb and Merck/MSD respectively, and approved for the treatment of diverse cancer types.

Today, I would like to review a versatile tool to conduct cell based inhibitor screenings on PD-1 / PD-L1/PD-L2 binding. [Read more…]

Easily customizable E3-ubiquitin ligase assay kits

08/02/2016 By Ali El Baya, PhD Leave a Comment

A ready-to-use E3 ligase activity enzymatic assay, the E3LITE kit, has been recently designed enabling researchers to screen for E3 enzyme inhibitors and potentially new therapeutical drugs. What’s it for and why is it of interest?

[Read more…]

IQF substrates for true isopeptidase/deubiquitinase activity measurement

05/02/2016 By Ali El Baya, PhD Leave a Comment

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.

[Read more…]