PhD project in Development of “beyond cysteine” chemical probes and focused screening libraries

Irreversible covalent inhibitors that target nucleophilic cysteine residues on disease-relevant POIs are well established with multiple covalent therapeutics in clinical use against targets such as Bruton’s tyrosine kinase (BTK) and epidermal growth factor receptor (EGFR). Much of the focus of recent targeted covalent inhibitor (TCI) research has centred around targeting reactive cysteine residues with much success as noted above. Given that cysteine has a relatively low proteome-wide abundance across potential binding sites and its high intrinsic nucleophilicity (leading to potential off-target toxicities) there is an emerging interest in developing complementary “beyond cysteine” approaches aimed at targeting other nucleophilic amino acid residues such as histidine, lysine and serine. This, it is believed will vastly expand the targetable proteome leading to next generation TCIs that can overcome resistance mechanisms (common with current TCIs) as well as offering new avenues for treating diseases of high unmet need.

The project will focus on the design, synthesis and validation of next generation “beyond cysteine” activity-based protein profiling probes (ABPPs) and focused electrophile screening libraries. Cysteine-targeting ABPPs are well established for use in chemoproteomic cysteine ligandability and screening exercises, however ABPPs targeting side-chain residues such as histidine and lysine are less well developed.
New ABPPs and focussed electrophile libraries will be developed and validated in collaboration with the newly established QUB/NI Chemoproteomic Centre-of-Excellence. Work within the McLaughlin group at QUB has established several new chemotypes with embedded electrophilic functionality, whose reactivity towards nucleophilic residues can be modulated through the modification of inherent electronic parameters. Several molecular scaffolds have been identified, based on ongoing work within the McLaughlin Lab, with distinct but complimentary reactivity profiles, each of these has the potential for wide ranging application in this area.
This approach differs from the current state-of-the-art as the molecular scaffolds have increased “3D-ness”, which is commonly under-represented in current screening libraries. Key to the successful implementation of this strategy will be the development of robust chemistries for the synthesis of each unique electrophilic motif, which will be the central objective of the project. Once chemistries have been developed the project team will evaluate the novel electrophilic molecules against non-cysteine residues (histidine/lysine etc) in relevant biophysical and biological assays.

Funding Information

This project is funded via QUB’s Enhanced Postgraduate Skills Doctoral Training Programme(EPS DTP) with industrial sponsorship from Almac. Almac Group is a global leader in providing a range of expert services and support across the drug development lifecycle.

UK studentships – cover tuition fees and include a maintenance stipend of £19,237 per annum.
This project offers an additional top-up stipend of £5,000 per year, and together with the maintenance stipend will give a take home pay of £24,237 per annum.
An industry gross salary (pre-tax, student loan repayment, pension (3%) and national insurance contributions) of £32,000 results in an approximately equivalent take home pay.
A UK studentship is open to UK and ROI nationals, and to EU nationals with settled status in the UK, subject to meeting specific nationality and residency criteria.
DfE studentship eligibility information can be viewed at: https://www.economy-ni.gov.uk/publications/student-finance-postgraduate-studentships-terms-and-conditions

Entrance requirements

Graduate
The minimum academic requirement for admission to a research degree programme is normally an Upper Second Class Honours degree from a UK or ROI HE provider, or an equivalent qualification acceptable to the University. Further information can be obtained by contacting the School.

International Students

For information on international qualification equivalents, please check the specific information for your country.

English Language Requirements

Evidence of an IELTS* score of 6.0, with not less than 5.5 in any component, or an equivalent qualification acceptable to the University is required (*taken within the last 2 years).

International students wishing to apply to Queen’s University Belfast (and for whom English is not their first language), must be able to demonstrate their proficiency in English in order to benefit fully from their course of study or research. Non-EEA nationals must also satisfy UK Visas and Immigration (UKVI) immigration requirements for English language for visa purposes.

For more information on English Language requirements for EEA and non-EEA nationals see: www.qub.ac.uk/EnglishLanguageReqs.