Design, synthesis and evaluation of novel polysialyltransferase inhibitors as anti- metastatic agents

Polysialic acid plays an essential role in neuronal development, but by adulthood is absent from the human body. Its biosynthesis is regulated by two polysialyltransferases (polySTs). Polysialic acid is aberrantly re-expressed on the surface of many tumours, where it plays a key role in diseases progression and metastasis. It is therefore an attractive anti-cancer target (see Current Cancer Drug Targets, 2012, 12, 925-939).

The ICT is focused on the development of novel polyST inhibitors, using computational chemistry to aid compound design. We have developed assays to assess compound inhibition (see Analyst, 2016, 141, 5849-5856) and have utilized tool compounds to show the potential of the approach (see PLoS ONE, 2013, 8, e73366). The wider project benefits from funding from programme funding from Yorkshire Cancer Research and more recently from the Wellcome Trust. The student will join a successful, motivated multidisciplinary team with expertise in medicinal chemistry, pharmacology and drug analysis.

The group has a series of hit polyST inhibitors with potential for further development. The project will focus on the synthesis of the next generation of inhibitors, utilising computational chemistry to aid compound design. Training in compound synthesis, purification (including preparative HPLC) and analysis (LC-MS, NMR) will be provided. Synthesised compounds will be evaluated in cell-free HPLC-based enzyme inhibition assay, with the most promising compounds then screened in cell-based assays, all in-house.