Group: Drug Discovery
Group Leader: Caroline Springer
Project Title: Proteolysis targeting chimeras (PROTACs): new approaches and applications to cancer
This 4 year PhD studentship offered in Professor Caroline Springer’s group is based at Alderley Park, Cheshire
The aim of the Drug Discovery Unit (DDU) is to discover new cancer drugs that utilise the fundamental discoveries made within the CRUK Manchester Institute (CRUK MI), the Manchester Cancer Research Centre, The University of Manchester and the wider research community. The DDU integrates medicinal, computational and synthetic chemistry with in vitro and cellular biology to provide new chemical entities for the treatment of unmet clinical need. Under the Directorship of Professor Caroline Springer, the Unit is actively progressing a portfolio of drug discovery projects against a variety of target classes in oncology disease indications.
PROTAC has emerged as a novel drug discovery strategy to achieve directed degradation of specific proteins within cells. Post-translational modification of proteins with ubiquitin chains is catalysed by ubiquitin ligases and is a key step in directing the respective proteins to proteasomal degradation. This approach creates alternative options to tackle traditionally “difficult to drug” proteins that are mutated or overexpressed in many cancers, and furthermore it leads to the removal of the target as opposed to inhibiting its catalytic function, potentially extending greatly the range of therapeutically tractable targets.
PROTACs are heterobifunctional molecules containing a target protein binder and an ubiquitin ligase binder connected by a linker. Dual binding of both components bring them in close proximity and initiate the ubiquitination followed by degradation. Several protein classes have been targeted successfully with PROTACs including transcription factors, kinases and epigenetic readers. The most commonly targeted ligases with PROTAC ligands are Cereblon and VHL. The nature and length of the linker between the two groups has a great impact on the efficacy of PROTACs.
There are several challenges to address in generating a successful PROTAC and its efficacy depends on the nature of the protein/ligase ligand pair, linkage site, linker length, and linker composition. An additional challenge is to generate compounds with cellular permeability and activity and eventually in vivo exposure and efficacy.
The aim of this studentship is to design and synthesise PROTAC molecules against targets with therapeutic potential in cancer, with initial focus on epigenetic modifiers such as SMARCA2, which is a key components of the SWI/SNF complex and is involved in chromatin re-modelling. The DDU has small molecule binders of one of the domains of the protein as well as suitable biological assays. The student will seek to optimise the PROTAC components, assisted by molecular modelling, and assess medicinal chemistry hypotheses for optimisation of the physicochemical and pharmacokinetic profile of these agents. A secondary aim of the studentship is to investigate and demonstrate proof of concept of less explored alternative PROTAC systems.
The successful candidate will learn synthetic and medicinal chemistry in the DDU and will become familiar with analytical chemistry, including the use of nuclear magnetic resonance, mass spectrometry and high performance liquid chromatography. The student will learn to use computational chemistry tools and knowledge of molecular modelling. He/she will gain an understanding of medicinal chemistry and drug design approaches and is expected to contribute and eventually take the lead on the design of new PROTACs. The student will also have the opportunity to learn biochemical and biological techniques such as enzymatic assays, cell culture and cell based assays.
This position is funded by Cancer Research UK for the 4 year duration. The successful candidate will join the CRUK Manchester Institute & will be affiliated to the University of Manchester on the same studentship terms and conditions as all CRUK MI students.
The successful applicant will be awarded a non-taxable & national insurance free annual stipend of £19,000/annum plus payment of university tuition and bench fees.
Closing date: Monday 3 December 2018 – 17:00 hrs GMT.
Interview date: Monday 14 January 2019, Alderley Park, Cheshire.