The development and evaluation of small molecule inhibitors of HUWE1 for the treatment of multiple myeloma

In multiple myeloma (MM) HUWE1 is dysregulated with HUWE1 protein expression increasing as the disease progresses resulting in further dysregulation of tumorigenic proteins. Previous small molecule inhibitors of HUWE1 have exhibited a high efficacy in vitro, however, are quickly metabolised in vivo.

Here a novel small molecule inhibitor of HUWE1 is described to act synergistically with current standard of care therapies: immunomodulatory drug lenalidomide and proteasome inhibitors bortezomib in both WT and mutant HUWE1 cell lines, as well as re-sensitising bortezomib and carfilzomib resistant cells to their respective proteasome inhibitors.<br><br><i>Thesis is embargoed until 31 July 2028.</i>