Bickmore, Wendy

Gilbert, Nicholas

Athmane, Naouel

2022-03-18T12:15:36Z

2022-03-18T12:15:36Z

2022-03-18

In 2020, cancer was the leading cause of early death in over 57 countries, accounting for approximately 10 million deaths worldwide. Brain cancers remain one example of greatest unmet need, with on average 14% survival 10 years post-diagnosis. Glioblastoma multiforme (GBM) is the most common and aggressive type of brain cancer in adults, with an average prognosis of 12 months. Current treatments only extended the average prognosis by 2 months. GBM is characterised by a complex set of mutations, with significant disruption to kinase pathways, specifically RTK signalling. Drug design in the past 30 years has predominately been target-based, focussing on the development of highly selective molecules that act against specific biological targets. Parallel to this, the rate of attrition – the number of compounds that fail in the clinics because of poor physicochemical properties – has greatly increased. For complex cancers, a targeted approach is not sufficient to discover new therapies. Phenotypic drug discovery, where compounds are designed based on defined pharmacological endpoints, without prior knowledge of the molecular target, was used to develop new compounds for the improved treatment of glioblastoma. Libraries of anticancer compounds based on the pyrazolo[3,4-d]pyrimidine scaffold have been designed for the treatment of glioblastoma. Compounds were synthesised in a convergent manner, and data from phenotypic screens against glioma cell-lines were used to build up structure-activity-relationships, facilitating further rounds of design and optimisation. Over 230 novel molecules were designed, synthesised, and screened, identifying several lead molecules with low-micromolar potencies. Further evaluation of lead molecules in cancer models and target deconvolution studies identified lead compounds that demonstrated preferential activity against the mesenchymal sub-type of glioblastoma. Whilst the target of the best lead compounds remains unknown, two selective inhibitors of CSF-1R kinase were identified through kinase screening.

https://hdl.handle.net/1842/38752

http://dx.doi.org/10.7488/era/2006

en

The University of Edinburgh

Comparing methods for visualising genomic loci in live mammalian cells

Thesis or Dissertation

Doctoral

PhD Doctor of Philosophy