XL80

XL80 is a preclinical small molecule molecular glue degrader developed by the National Cancer Institute (NCI) and the National Heart, Lung, and Blood Institute (NHLBI). It is a structure-guided derivative of XL44 designed to target and deplete hRpn13Pru, a post-translationally processed form of the 19S proteasome regulatory subunit ADRM1 (Rpn13). XL80 also targets other KEN box-containing proteins, such as PCLAF and RRM2, for degradation without requiring fusion to an E3 ligase ligand. In preclinical models of multiple myeloma and breast cancer, XL80 disrupts the ubiquitin-proteasome system, activates the spindle assembly checkpoint (SAC), inhibits the anaphase-promoting complex/cyclosome (APC/C) pathway, and impairs microtubule dynamics, leading to mitotic arrest and apoptosis.