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 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.