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

Abstract

HUWE1 is a large HECT domain containing E3 ligase which is involved in the regulation of tumorigenic proteins including Mcl-1, p53, and c-Myc either through the ubiquitin proteasome system (UPS), or protein stabilisation. 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.

Thesis is embargoed until 31 July 2028.

Date of Award	Jul 2024
Original language	English
Awarding Institution	Queen's University Belfast
Sponsors	Leukaemia & Lymphoma NI
Supervisor	Richard Williams (Supervisor) & Lisa Crawford (Supervisor)