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Targeting the cancer – approaches to the design and synthesis of new anti-cancer agents (SEARCEYMU20SCIPVC)


Project Description

The last few years have seen the introduction to the clinic of antibody-drug conjugates or ADCs that have revolutionised the treatment of some cancers.1 They enable the targeting of highly potent molecules to their site of action- the tumour cell – so that side effects should be diminished as off target effects are reduced. Most of these potent molecules are derived from natural products that could not be used therapeutically were it not for the targeting effect. We have carried out extensive studies on a family of natural products known as the duocarmycins and others have progressed these molecules as ADCs with the first clinically used compound currently being tested in patients in Phase II trials.2 ADCs suffer from a number of drawbacks, associated with the chemistry of the potent molecules, the chemistry of the linkers and the conjugation of the molecule to the antibody to form the ADC. For example, attachment of hydrophobic molecules to the antibody leads to unfavourable aggregation and physiochemical issues. Release of the potent molecule by the linker prior to entry into the cell leads to off-target effects. Finally, conjugation to the antibody varies in efficiency and reaction site such that even the clinically used agents have variations in drug molecule attached to the ADC from one to four adducts.

This PhD project will extend our previous studies on the duocarmycins. Using methods developed in the laboratory,3 we have the ability to tune the physicochemical properties of these ultrapotent molecules so that, on conjugation, aggregation will not occur. We will also investigate methods for conjugation that are more precise that current approaches. We have also investigated small molecule drug conjugates (SMDCs)4 and peptide drug conjugates (PDCs), alongside nanoparticle based approaches and will use all of these to enhance the ability of the duocarmycins to progress towards extensive clinical use.

For more information on the supervisor for this project, please go here: https://people.uea.ac.uk/m_searcey?_ga=2.157816826.1750114613.1580721734-1542410998.1555514315

This is a PhD programme.

The start date of this project is October 2020.

The mode of study is full-time, studentship length is 3 years.

Entry requirements: Acceptable first degree in Chemistry, pharmacology and drug discovery, pharmacy or related. The standard minimum entry requirement is 2:1.

Funding Notes

This PhD project is funded by the Faculty of Science for 3 years. Funding is available to UK/EU applicants and comprises home/EU tuition fees and an annual stipend of £15,009 for 3 years. Overseas applicants may apply but they are required to fund the difference between home/EU and overseas tuition fees (which for 2019-20 are detailed on the University’s fees pages at View Website . Please note tuition fees are subject to an annual increase).

References

1. Thomas A, Teicher BA, Hassa R (2016). Antibody drug conjugates for cancer therapy. Lancet Oncology 17, e254-e262.

2. Beekman AM, Cominetti MMD, Searcey M (2019). Duocarmycins as antibody-drug conjugate (ADC) payloads. Cytotoxic payloads for Antibody Drug Conjugates in RSC Drug Discovery Series, 71, 187-208.
3. Stephenson MJ et al (2015). Solid-phase synthesis of duocarmycin analogues and the effect of C-terminal substitution on biological activity. J. Org. Chem 80, 9454-9467.

4. Beekman AM, Cominetti MMD, Cartwright OC, Boger DL, Searcey M (2019). A small molecule drug conjugate (SMDC) of DUPA and a duocarmycin built on the solid phase MedChemComm 10, 2170-2174.

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