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A Chemical Biological Platform to Interrogate the Mechanisms of Anti-Cancer Activity of Splice-Switching Small Molecules


   Department of Pure and Applied Chemistry


About the Project

Background

 

Alternative RNA splicing is an extraordinary process that generates proteomic diversity (estimated at up to 150,000 human proteins) from only 20,000 human genes. More than 90% of human genes use splicing to produce on average multiple protein isoforms, sometimes with antagonistic functions, to be expressed from a single gene. However, mutations affecting splicing can result in the onset of disease such as cancer. A prominent example is the aberrant splicing of the Bcl-X gene which is an apoptotic checkpoint. Bcl-x pre-mRNA encodes two isoforms with antagonistic functions. The major protein isoform (Bcl-xL) displays anti-apoptotic functions and is overexpressed in most cancer cells. Overexpression of the alternative protein isoform (Bcl-xS) results in caspase-mediated apoptotic cell death.

In collaboration with colleagues in Leicester (Ian Eperon and Cyril Dominguez), we have identified a small molecule (GQC-05) which induces a switch in Bcl-X splicing towards the pro-apoptotic Bcl-xS pre-mRNA isoform. Whilst GQC-05 displays potent anti-cancer in live cells, the exact molecular mechanisms of splice-switching action are currently unknown.

Project objective

The overall objective of this PhD studentship is to establish a chemical biological platform to interrogate the molecular mechanisms of splice-switching. This will involve the development of new synthetic methodology to establish structure-activity-relationship profiling of GQC-05. The synthesis of chemical biological probes will also be developed that will assist in the identification of protein and RNA-binding partners of these splice-switching small molecules by mass spectrometry-based proteomics analysis in collaboration with Dr Nik Rattray.

This project will involve the development of novel chemical probes involved in protein and RNA identification, new mass spectrometry and activity-based protein profiling techniques to aid identification of binding partners, and in collaboration with our colleagues in Leicester, assisting in the identification of new chemotypes for suitable for further development as next-generation anti-cancer agents.

Academic Environment

The student undertaking this project will receive unparalleled training in synthetic chemistry, chemical biology as part of Strathclyde Centre for Molecular Bioscience, a new centre of excellence at the chemistry-biology interface. The Burley group has extensive experience in small molecule and nucleoside synthesis, solid phase peptide/nucleic acid synthesis, chemical biological probe development and bioconjugation. The student will also receive training in the Rattray group in novel mass spectrometry methods for identifying biomolecular interactions for proteomic profiling.

This is an EPSRC Industrial CASE studentship in collaboration with GlaxoSmithKline (GSK). In addition to our Glasgow-based collaboration, the successful applicant will be expected to spend at least 3 months working alongside chemical biology groups at GSK’s Stevenage site.


Funding Notes

This studentship is open to UK and international students, and includes a stipend and fees for 4 years. Candidates must have a strong background in Synthetic Organic or Medicinal/Biological Chemistry and have obtained a (i) or 2(i) [or equivalent for EU students] degree.
Candidates who are interested in this position are encouraged to send their CV and contact details of two referees to .

References

1. Campbell, E.; Taladriz-Sender, A.; Paisley, O.I.; Kennedy, A.R.; Bush, J.; Burley, G.A. “A Chemo- and Regioselective Tandem [3+2]Heteroannulation Strategy for Carbazole Synthesis: Synergizing Two Mechanistically Distinct Bond-Forming Processes” Journal of Organic Chemistry 2022, 87, 4603.
2. Taladriz-Sender, A.; Campbell, E.; Burley, G.A. “Splice switching small molecules: a new therapeutic approach to modulate gene expression” Methods, 2019, 167, 134.
3. Weldon. C.; Behm-Ansmant. I.; Hurley. L.H.; Burley. G.A.; Branlant. C.; Eperon. I.C.; Dominguez. C. "Specific G-quadruplex ligands modulate the alternative splicing of Bcl-X" Nucleic Acids Research, 2018, 46, 886.
4. Jobbins, A.M.; Reichenbach, L.F.; Lucas, C.M.; Hudson, A.J.; Burley. G.A.; Eperon. I.C. “The mechanisms of a mammalian splicing enhancer” Nucleic Acid Research, 2018, 46, 2145.
5. Weldon, C.; Behm-Ansmant, I.; Hurley, L.H.; Burley, G.A.; Branlant, C.; Eperon, I.C.; Dominguez, C. "Identification of G-quadruplexes in functional RNAs using FOLDeR" Nature Chemical Biology, 2016, 13, 18.

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