Exploring the potential of ubiquitin UBE2D inhibitors as novel anti-cancer treatments

Many widely used cancer chemotherapeutics are unspecific and have strong side effects. Therefore, it is essential to develop novel anti-cancer strategies, targeting pathways that only cancer -and not normal- cells rely on. In this context, enzymes of the DNA damage response (DDR) are of great interest: many cancers feature DDR alterations, making them more sensitive to inhibition of individual DDR pathways. Inhibition of ubiquitin enzymes is particularly interesting in this regard, as many ubiquitin enzymes are potentially druggable and have emerged as crucial DDR players. As such, UBE2D enzymes are important for DNA repair by homologous recombination, highlighting their potential as novel anti-cancer drug targets, for instance in ovarian cancers. These cancers of unmet needs often harbour defects in DDR pathways. Importantly, a first UBE2D inhibitor, sesquiterpene lactone IJ-5, has recently been discovered. However, due to extensive purification requirements, only a few mg of this natural product have been isolated to date. This greatly limits our ability to test IJ-5 and structural analogues as UBE2D inhibitors, and as novel anti-cancer treatments.

To overcome this limitation, our aim is to synthesise IJ-5 and related analogues inspired by this structure, and test their potential as UBE2D inhibitors. The first objective will be to synthesise IJ-5 and a set of analogues determined by computational docking methods, involving the development and application of innovative organic synthetic and medicinal chemistry techniques. The second objective will be to test these compounds in in vitro ubiquitylation assays and take the most promising compounds forward for studies in control, and appropriate cancer cell lines, known to harbour different DDR defects. The student will then define the situations where IJ-5/analogues hypersensitise cancer cells through synthetic lethality and/or other mechanisms. In a complimentary approach the student will delete UBE2Ds (four highly related enzymes) individually or combined, using state-of-the-art CRISPR/Cas9 gene targeting methods. Training will be provided for tissue culture and a wide range of cell biology, biochemistry, biophysics and imaging methods.

These cross-disciplinary studies will lead to novel methodologies in chemical synthesis, deepen our molecular understanding of UBE2Ds in the DDR and during carcinogenesis, and might open up new rationalised ways of treating cancer.