Novel Ruthenium Catalysts for Drug Discovery of DNA Damage Response Inhibitors

The DNA Damage Response (DDR) harbours a plethora of eminently druggable targets that could lead to the treatment of cancer, ageing and associated diseases. However, despite the advances in biological understanding, progress has been slow in finding and optimising suitable small molecule drugs for many of these targets. This is partially due to the narrow section of chemical shape space that is currently commonly explored in the drug discovery process, due to the overreliance on a very small set of reactions that have traditionally been favoured over the past 20 years. In recent years, C-H functionalization has emerged as an extremely promising new synthetic tool that could accelerate drug discovery by allowing fast access to new chemical space through the direct modification of existing drugs or biologically active molecules at their C-skeleton structure. However, the adaptation of C-H functionalisation tools to achieve this proposed ‘late-stage functionalisation’ faces major challenges in that most transition metal catalysts are incompatible with the highly polar functionalities present in biologically active molecules.

In a collaborative effort between the Schmidt group at the Manchester Cancer Research Centre (MCRC), the Larrosa group at the School of Chemistry and the Tabernero group in the Michael Smith Building (MSB), this project will focus on the development of a new class of ruthenium-catalysts recently discovered in the Larrosa group, which are able to carry out late-stage C-H functionalisation on heavily functionalised molecules such as pharmaceuticals, biologically active molecules and drug candidates. These catalysts will be used to create novel libraries of drug candidates across currently barely explored chemical shape space with the aim of targeting DNA repair pathways.

The successful applicant will receive state-of-the-art training on all aspects of the project, including organometallic chemistry, catalysis, synthetic chemistry, generation of compound libraries and on drug discovery approaches. Moreover, the appointee will be trained in the biological aspects of the work, such as cell proliferation, DNA repair and biochemical assays, as well as tissue culture tech-niques and advanced microscopy approaches.