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The freedom of academic research

We get projects requiring high-throughput screening of small molecules from a wide variety of areas. This reflects the eclectic nature of projects that the team has been working on. While cancer-related projects still represent about 40% of the unit’s work-load, some projects relates to inflammation, neurodegeneration, metabolic disease, and other areas.

This is typical of an academic environment, where free and unencumbered thinking allows scientists to tackle interesting basic research questions underlying disease mechanisms. Such research would be prohibitive in a biotech or Pharma environment, which has more constrained goals related to marketing and production. This is one reason Pharma turns to academia for fresh ideas in areas of unmet medical need.

 

Working with screening systems

Biological samples can be difficult to examine and compare due to the heterogeneous nature of cells and tissues. The effects of chemical compounds or drugs on the shape and behavior of cells can be very subtle. The “high content” imaging system enables rapid and reproducible acquisition of high-resolution images of cells after treatment with chemical compounds.

This process can be repeated thousands of times a day during a high-content screen. The basis of this technology is a fluorescent wide-field microscope coupled with a high-resolution confocal microscope. Using the confocal ability increases the image resolution from multi-layer specimens, such as complex tissue cultures or organoids.

Our screening systems, installed in 2017, is enabling higher precision measurements and visualization of fluorescently tagged proteins. 

New: robotics

Investments in state-of-the-art instrumentation enabled a more productive workflow in the lab.
In 2017, the addition of a second Echo 555 liquid handler, based on acoustic dispensing technology, resulted in the doubling of our capacity to deliver compounds into microtiter plates for screening and follow-up work. As a result, compound screening can be performed with greater precision, either in one concentration or arrayed in dose response.

In addition, a new vial-handling robot will be installed soon to streamline incorporation of new compounds synthesized in medicinal chemistry.

Identifying proteins in breast cancer

High-throughput drug discovery involves testing tiny amounts of different chemical and biochemical compounds – out of the 100,000 such compounds in the lab’s library – to see if any interact with particular proteins or other biological materials. These tests can involve all of the compounds in the library or any subset, and automated assay equipment can test them all in short order.

The Wohl Drug Discovery unit has participated in research led by Prof. Yosef Yarden from the Department of Biological Regulation. Prof. Yosef Yarden. Yarden and his colleagues had identified a protein that is overexpressed in certain aggressive breast cancers and that helps them metastasize and turn deadly. In the lab dish one can knock out genes and see what happens to the cancer, but genetic manipulation is not yet an option for the human body. The question was: is this protein a so-called drug-able target? Can it be blocked, and will blocking it help to prevent metastasis? Screening in the Maurice and Vivienne Wohl Institute for Drug Discovery revealed several inhibitors of this protein, and further trials in Weizmann Institute labs showed that these inhibitors prevent the cancer cells from breaking out of the tissue that hold them in place. These findings have now been passed on to a pharmaceutical company for further research and development.

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Searching for NF-kB inhibitors

The NF-kB family of transcription factors (TFs) plays key roles in immune and stress responses and its deregulation contributes to several diseases. Therefore, its modulation has become an important therapeutic target.

As part of the collaboration with Prof. Rivka Dikstein from the department of bimolecular sciences, the Wohl Drug Discovery unit performed a high throughput screening (HTS) campaign against the G-INCPM compound library to identify compounds that inhibit the dimerization of the NF-kB protein p65.

Shaked Ashkenazi, a student in Prof. Dickstein’s lab, has developed a screening assay and transferred it to Dr. Alexander Plotnikov, in the Wohl Drug Discovery unit. The screening campaign identified, among other “hits”, a natural product by name of Withaferin A, a documented anti-cancer and anti-inflammatory compound whose mechanism of action was unknown. Computational modeling by Dr. Efrat Ben Zeev in the Ilana and Pascal Mantoux Institute for Bioinformatics team suggested a novel mechanism of interaction between the compound and the p65 dimers, likely explaining the compound’s ability to interfere in the dimerization. These novel results establish TF dimerization as a drug target.

This study was published in the prestigious journal Molecular and Cellular Biology under the title “A novel allosteric mechanism of NF-kB dimerization and DNA binding targeted by an anti-inflammatory drug”, by S. Ashkenazi, A. Plotnokov, A. Bahat, E. Ben-Zeev, S. Warzawski and R. Dikstein.

Image credit: American Society for Microbiology/ Shaked Ashkenazi et al. Mol. Cell. Bio. 2016`36:1237-1247  

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