In vivo KRAS G12D/V Degradation Mediated by CANDDY Using a Modified Proteasome Inhibitor

Abstract

"Undruggable" proteins, such as RAS proteins, remain problematic despite efforts to discover inhibitors against them. KRAS mutants are prevalent in human cancers. Recently, the KRAS G12C inhibitor have been clinically approved, but inhibitors for KRAS G12D/V are still under development. Here, we described the development of a novel chemical knockdown strategy, termed CANDDY (Chemical knockdown with Affinity aNd Degradation DYnamics). This strategy involves a CANDDY tag modified from a proteasome inhibitor inducing direct proteasomal degradation. We constructed TUS-007 as a multispecific small molecule tethered from a KRAS interactor and CANDDY tag to target KRAS G12D/V. We confirmed that the degradation by TUS-007 was independent of target ubiquitination. This allows to solve a laborious design of matchmaker in the current ubiquitination-dependent proteolysis technology. And TUS-007 successfully suppressed tumors due to in vivo degradation of KRAS G12D/V. The CANDDY technology could represent a simple and rational strategy to degrade currently "undruggable" proteins.