Developing inhibitors of tankyrase protein-protein interactions

The human Tankyrase proteins (TNKS & TNKS2) are members of the poly(ADP-ribose) polymerase (PARP) family that catalyse the addition of poly(ADP-ribose) (PAR) chains onto substrate proteins. The PAR chains can either, directly regulate substrate function, recruit PAR-binding effector proteins, or, as a specific example of the latter, mark PARylated proteins for degradation. Tankyrase PARylates many proteins implicated in the development and maintenance of cancer. Pharmacological tools for the inhibition of Tankyrase have so far been restricted to inhibitors of the catalytic PARP domain. Recently, the Guettler group have shown that the scaffolding effects of Tankyrase are critical, and that PARP domain inhibitors achieve only partial modulation of Tankyrase function. Potent, cell-active small molecule chemical tools are required to further investigate the consequences of inhibiting Tankyrase-substrate interactions and to provide potential starting points for drug discovery. We have applied fragment-based screening to find low-molecular-weight small molecules that interact with the substrate binding groove in the Tankyrase ankyrin repeat clusters (ARCs). The aim of this project is to develop these chemical starting points into potent, cell-permeable small molecule inhibitors of Tankyrase substrate binding, using structure-based fragment optimisation and fragment growing approaches. The student will measure compound affinity using ligand- and protein-based NMR techniques and use these data to construct in silico models of compound binding. New molecules with additional specific interactions in the binding site will be designed, synthesised and tested by the student. The project will also investigate crystallisation of the compounds bound to Tankyrase ARCs using protein constructs and crystallisation conditions established in our laboratories. When potent compounds are identified, the student will optimise the physicochemical properties to give high solubility and membrane permeability, consistent with cellular activity. The effects of optimised compounds on Tankyrase function in cancer cells will be assessed in assays established in Dr Guettler’s laboratory.

Candidate profile
Candidates must have a first class or upper second class honours BSc Honours/ MSc or MChem or equivalent in Chemistry or Medicinal Chemistry, incorporating laboratory-based training in synthetic chemistry

How to apply
Full details about these studentship projects, and the online application form, are available on our website, at: www.icr.ac.uk/phds Applications for all projects should be made online. Please ensure that you read and follow the application instructions very carefully.

Closing date: Monday 20th November 2017
Applicants should be available for interview 29h and 30th January 2018.

Please apply via the ICR vacancies web portal https://studentapps.icr.ac.uk/

Download a PDF of the complete project proposal:
https://d1ijoxngr27nfi.cloudfront.net/default-document-library/collins-guettler-2017-icr-studentship-proposal-web.pdf