Description
Rpn13 degrader WL40 (WL40) is a novel covalent ubiquitin receptor Rpn13 degrader by linking the Rpn13 covalent inhibitor RA190 with the cereblon (CRBN) binding ligand thalidomide; binds to both Rpn13 and CRBN and triggers degradation of cellular Rpn13; WL40 decreases viability in MM cell lines and patient MM cells (IC50=400-750nM), even those resistant to bortezomib, WL40 interrupts Rpn13 function and activates caspase apoptotic cascade, ER stress response and p53/p21 signaling; inhibits xenografted human MM cell growth and prolongs survival in animal model studies