Identifying Biologically Relevant, Non-Teratogenic Analogs of Thalidomide to Understand and Combat the Inflammatory Response and its Disorders

Supervisory team: Dr Neil Vargesson and Professor Cosimo de Bari

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. However, tragically, a new generation of thalidomide-damaged children are now being observed in Brazil where the drug is used to treat leprosy. This project is focused on identifying and then screening new analogs of thalidomide that retain the clinically relevant aspects but not the teratogenic side-effects which is due to the drug’s actions on blood vessel formation (Beedie et al., 2015; Beedie et al., 2016; Therapontos et al., 2009). The Vargesson lab (Cell, Developmental & Cancer Biology programme) has previously identified and patented eleven thalidomide analogs with anti-inflammatory only actions. First, using our published assays (Beedie et al., 2015; Beedie et al., 2016), over 35 new and novel thalidomide analogs, based on our patented analogs, will be screened to identify their actions and identify more analogs with anti-inflammatory and non-teratogenic actions. Second, the potent anti-inflammatory only analogs will then be screened in clinically relevant human cell-based assays and pre-clinical mouse models of arthritis (Kurth et al., 2011; Redelinghuys et al., 2016) (in collaboration with Professor Cosimo de Bari (Arthritis & Musculoskeletal Medicine programme) to confirm their action(s) and investigate their use as a treatment of arthritis, a debilitating condition affecting joints due to inflammation. The student will also analyse molecular pathways related to the inflammatory response and determine molecular targets of the analogs.