Screening Thalidomide Analogs to Identify Anti-Inflammatory Specific Compounds to Combat the Inflammatory Response and its Disorders

Thalidomide notoriously caused birth defects to thousands of children in the 1960s where it was used to treat morning sickness. Thalidomide is now used to effectively treat leprosy and multiple myeloma. Leprosy in particular is a major health problem in South America and equatorial regions of the world. Effective treatments are very few. However, tragically, a new generation of thalidomide-damaged children are now being observed in Brazil where the drug is used to treat leprosy but is not controlled as it is in the UK, USA, Europe and Australia.

This project is focused on identifying and screening new analogs and breakdown products of thalidomide that retain the clinically and biologically relevant aspects but not the side-effects. The Vargesson lab has previously identified thalidomide’s action in destroying blood vessels as the cause of the birth defects, so this project aims to identify analogs that retain anti-inflammatory actions only (Beedie et al., 2015; Beedie et al., 2016; Therapontos et al., 2009). In addition the project will shed light on molecular pathways influenced by these compounds that result in anti-inflammatory response to help better understand this process (which is essential in normal development and normal adult life – such as wound healing).

Using our published assays using zebrafish and chicken embryos as well as in-vitro cell culture assays (Beedie et al., 2015; Beedie et al., 2016), novel thalidomide analogs and breakdown products will be screened to identify their actions and identify those with anti-inflammatory and non-teratogenic actions. Such identified analogs will then be screened in human cancer and inflammatory tissue culture assays to confirm their actions. Additionally any potent anti-inflammatory analogs identified may also be screened in animal models of inflammation to confirm their action(s). The student will also analyse molecular pathways related to the inflammatory response in embryos and determine molecular targets that the analogs target.