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Exploiting cyclic dipeptides as improved anticancer therapeutics


Project Description

Background and project details: Lung cancer is the most common cause of cancer deaths in both males and females. In the UK, of the total deaths caused by cancer 21% are caused by lung cancer alone. It is also a global problem, with approximately 1.8 million cases diagnosed every year.

In the last 70 years almost half of all small molecules approved for cancer treatment were natural products or molecules derived from natural products. Cyclic dipeptides are natural products that possess anticancer activity. One of such molecules, Plinabulin, is under a worldwide clinical trial for the most common form of lung cancer, i.e. non-small cell lung cancer.
Cyclic dipeptides are a privileged class of molecules since they are stable to high temperature and degradation by our body, are easily absorbed by our gut and can penetrate the blood-brain-barrier.

The overarching goal of the project is to develop and evaluate novel compounds derived from Plinabulin as anti-cancer agents. Because large empty hydrophobic pockets can be observed when Plinabulin interacts with its main target[1], we hypothesize that using our novel approach and methodology more specific compounds can be produced, which will be more potent and less toxic. In the future, these molecules can be further developed into drugs or become drugs themselves.

Expected outcomes for student:
1) Generation of small library of modified cyclic dipeptides by assembling enzymatic cascades in vitro using a combination of tRNAs and enzymes as required.
2) Evaluation of cyclic dipeptides produced against a panel of five cancer cell lines. This part of the work will be done in Prof David Harrison’s laboratory in the School of Medicine of St Andrews, across the street from the Czekster lab.
3) Pull down experiments using cell extracts followed by mass spectrometry to confirm cyclic dipeptides are binding to their original targets and determine any off-target effects or potential changes in mechanism of action.

Techniques and training: The Czekster laboratory routinely utilizes x-ray generators, liquid dispensing robots, automated crystal imaging instrumentation, plate readers capable of UV, fluorescence and luminescence readings, high pressure liquid chromatography (HPLC) and fast protein liquid chromatography (FPLC), a biophysics suite containing a stopped-flow apparatus, circular dichroism, isothermal titration calorimetry, and surface plasmon resonance instruments. [2] This expertise and instrumentation covers all bases for small molecule production, characterization, as well as biochemical and biophysical assays that the project requires. Student will acquire training in most, if not all, of these techniques.

When in the School of Medicine, the student will be trained by experienced researchers in the Harrison group, with expertise in cell biology, imaging, immunohistochemistry, pathology, cellular functional assays, as well as in procedures to culture and maintain cancer cell lines.

-Technical skills: in enzymology, assay development, chemical and structural biology, biophysical techniques, cancer pathology and functional assays, mass spectrometry.
-Analytical skills: design and interpret experiments, as well as write manuscripts, prepare and deliver talks.
-Communication skills: student will present their work to diverse audiences, and will be expected to attend and present at one international conference during their PhD.
-Engagement with the public: The Czekster lab currently runs a public engagement program with primary schools, and the student will have the opportunity to take part.
-Career development: university offers access to the program GRADskills, a suite of workshops, networking events and activities designed for research postgraduate students and delivered by the Centre for Academic, Professional and Organisational Development (CAPOD). Student will be encouraged to take part.

Applicants are encouraged to contact the PI, Clarissa Czekster, prior to application by e-mail () with any questions or to discuss further details of the project.

Funding Notes

UK/EU citizens, funded by the Cunningham Trust, duration: 3 years.

References

[1] Wang Y. et al (2015) FEBS J 283:102-111.
[2] Czekster C. M.et al (2017) Nature Communications 8:1045.


How good is research at University of St Andrews in Biological Sciences?

FTE Category A staff submitted: 50.45

Research output data provided by the Research Excellence Framework (REF)

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