Phd - Developing a novel methotrexate-derived small molecule JAK/STAT pathway inhibitor

"Work in the Zeidler lab has previously identified the anti-folate drug methotrexate (MTX) as a potent JAK/STAT pathway inhibitor. Used at low doses for the treatment of inflammatory and autoimmune conditions such as rheumatoid arthritis, methotrexate is widely used, has a well understood toxicity profile and is a very low cost drug. Given its function as a JAK/STAT inhibitor, the potential exists to repurpose MTX for other diseases associated with inappropriate pathway activity. Such a change in clinical practice has recently been demonstrated and has significant potential to fulfill a significant unmet need.
However, while repurposing MTX has considerable potential, its long term use is also sometimes associated with potentially serious side-effects – most of which are the consequence of its inhibition of dihydrofolate reductase activity (DHFR). MTX side effects range from relatively minor gastro-intestinal discomfort and nausea to potentially serious myelosuppression and foetal loss/defects in early pregnancy. Given these undesirable characteristics, the development of novel MTX-derived compounds which retain their ability to suppress the JAK/STAT pathway, but which no longer inhibit DHFR, have the potential to define a new class of ‘next generation’ JAK/STAT pathway inhibitors.
In this project, cell based assays for JAK/STAT and DHFR activity already established in the Zeidler lab will be combined with novel medicinal chemistry approaches in the Partridge lab. The successful candidate will design and synthesize libraries of novel MTX derivatives designed to explore the chemical space around methotrexate. The candidate will then use these compounds, together with established positive and negative controls, to undertake cell based assays designed to establish the specificity, activity and toxicity of the molecules generated. Lead compounds will be refined using iterative ‘molecular evolution’ approaches and established medicinal chemistry techniques. Ultimately, compounds will be tested in pre-clinical Drosophila and mouse models of human JAK/STAT disease. In the long-term, we aim to engage with the pharmaceutical industry as a prelude to potential human clinical trials.
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Funding Notes

Applications from self-funded students or students with secured funding are also welcome.
Entry requirements
First class or upper second 2(i) in a relevant subject. To formally apply for a PhD Studentship, you must complete the University's application form using the following link: http://www.sheffield.ac.uk/bms/prospective_pg/how_to_apply
*All applicants should ensure that both references are uploaded onto their application as a decision will be unable to be made without this information*.

References

"Thomas S, Fisher KH, Snowden JA, Danson SJ, Brown S, Zeidler MP (2015) “Methotrexate is a JAK/STAT pathway inhibitor” PLOSone 10(7) e0130078

Palandri, Francesca; Labate, Claudia; Sabattini, Elena; et al. (2016) “Low-dose methotrexate as treatment of myeloproliferative neoplasms: Proof of principle of clinical activity” Am J HEMATOLOGY 91(8) E329-E330
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