Deubiquitinase-Targeting Chimeras Mediated Stabilization of Tumor Suppressive E3 Ligase Proteins as a Strategy for Cancer Therapy

Targeted protein stabilization has emerged as a promising therapeutic strategy to combat various human diseases linked to aberrant protein degradation. However, the deubiquitinase-targeting chimera (DUBTAC) technology is still in its infancy, with only a few proteins being successfully stabilized. To this end, the stabilization of tumor suppressor proteins represents a critical therapeutic strategy to combat cancer, as their loss-of-function mutations and reduced expression are frequently implicated in the pathogenesis of diverse types of human cancer. In this study, we present an innovative PRO–DUBTAC platform that, for the first time, stabilizes tumor-suppressive E3 ubiquitin ligases as a novel anticancer therapeutic approach. Through the conjugation of E3 ligase ligands with a small-molecule ligand of the deubiquitinase OTUB1 via a linker, we developed two series of PRO–DUBTACs─VHL-DUBTAC and KEAP1-DUBTAC─that effectively stabilize the tumor-suppressive E3 ligases VHL and KEAP1 in cells, respectively, in an OTUB1-dependent manner to retard tumor cell growth. PRO–DUBTAC could be a versatile and generalizable platform for the selective stabilization of tumor-suppressor E3 ligases, thereby opening new therapeutic avenues for targeted cancer therapies by harnessing the tumor-suppressive potential of E3 ligases.