PT  - JOURNAL ARTICLE
AU  - Imanishi, Satoshi
AU  - Huang, Lijuan
AU  - Itakura, Shoko
AU  - Ishizaka, Masamichi
AU  - Tsukamoto, Megumi
AU  - Saito, Megumi
AU  - Iwasaki, Yoichi
AU  - Yamaguchi, Tomohiro
AU  - Miyamoto-Sato, Etsuko
TI  - <em>In vivo</em> KRAS G12D/V Degradation Mediated by CANDDY Using a Modified Proteasome Inhibitor
AID  - 10.1101/2021.04.23.441075
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.04.23.441075
4099  - http://biorxiv.org/content/early/2021/04/23/2021.04.23.441075.short
4100  - http://biorxiv.org/content/early/2021/04/23/2021.04.23.441075.full
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.