Medicinal Chemistry PhD Project: Synthesis and biological evaluation of small molecules to target mesothelioma and related ASS1-dependent tumours

Arginine (Arg) is an amino acid critically involved in numerous biological functions including cell proliferation, cell signaling, muscle contraction, immunity, neurotransmission, vasodilation and the synthesis of growth factors and other amino acids. It is considered as a non- or semi-essential amino acid, due to the intrinsic ability of ‘normal cells’ to synthesise arginine from citrulline and aspartate via argininosuccinate synthase 1 (ASS1) and argininosuccinate lyase (ASL) in addition to dietary intake. ASS1, which as part of this process catalyses the reaction of L-citrulline and aspartate to argininosuccinate, is the rate-limiting enzyme for the biosynthesis of arginine.

One of the most common metabolic defects of tumour cells is the impaired intrinsic ability to synthesise arginine. Malignant melanoma, hepatocellular carcinoma, mesothelioma, and prostate cancer are virtually ASS1-silenced, whereas about 40%–60% of breast cancers, small-cell lung cancers, pancreatic and leukemias are ASS1-negative. These tumors all use extracellular arginine for their survival. Therefore it is unsurprising that arginine-deprivation approaches are becoming increasingly popular as potential therapies to treat a variety of cancers.

This is a multidisciplinary project applying chemical synthesis and biological testing to design, synthesise and biologically evaluate new small molecules which can interfere with arginine-dependent tumours. Instead of an arginine-deprivation approach, the project proposes to utilise the inherent need of the tumour for extracellular arginine and to use this to deliver a toxic moiety to the tumour; in other words we will use the arginine structural motif as a targeting system to deliver a highly potent anti-cancer agent directly to the tumour. This approach would be particularly efficient after a period of arginine starvation i.e. treatment with ADI-PEG20, as the tumour would immediately sequester the arginine-tagged compound after administration. Initially, platinum-containing moieties would be incorporated given their partial success against the ASS1-negative tumours.

The project would be ideally suited for someone with a strong chemistry background and an interest and expertise in organic chemistry and the desire to learn molecular biology assay techniques.