RT Journal Article SR Electronic T1 In vivo KRAS G12D/V Degradation Mediated by CANDDY Using a Modified Proteasome Inhibitor JF bioRxiv FD Cold Spring Harbor Laboratory SP 2021.04.23.441075 DO 10.1101/2021.04.23.441075 A1 Imanishi, Satoshi A1 Huang, Lijuan A1 Itakura, Shoko A1 Ishizaka, Masamichi A1 Tsukamoto, Megumi A1 Saito, Megumi A1 Iwasaki, Yoichi A1 Yamaguchi, Tomohiro A1 Miyamoto-Sato, Etsuko YR 2021 UL http://biorxiv.org/content/early/2021/04/23/2021.04.23.441075.abstract AB “Undruggable” proteins, such as RAS proteins, remain problematic despite efforts to discover inhibitors against them. KRAS mutants are prevalent in human cancers. Although KRAS G12C inhibitors have been developed recently, there are no effective inhibitors for KRAS G12D/V. Here, we described the development of a novel chemical knockdown strategy, termed CANDDY (Chemical knockdown with Affinity aNd Degradation DYnamics). This strategy, which is not an inhibition strategy, involves a CANDDY tag modified from a proteasome inhibitor. The tag induces 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. TUS-007 successfully suppressed tumors due to the degradation of KRAS G12D/V. We confirmed that the CANDDY tag-induced degradation was independent of target ubiquitination. The CANDDY technology could represent a simple and practical way to degrade currently “undruggable” proteins.Competing Interest StatementThe authors have declared no competing interest.