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 Satoshi Imanishi A1 Lijuan Huang A1 Shoko Itakura A1 Masamichi Ishizaka A1 Yoichi Iwasaki A1 Tomohiro Yamaguchi A1 Etsuko Miyamoto-Sato YR 2021 UL http://biorxiv.org/content/early/2021/11/22/2021.04.23.441075.abstract AB “Undruggable” proteins, such as RAS proteins, remain problematic despite efforts to discover inhibitors against them. KRAS mutants are prevalent in human cancers. 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.Competing Interest StatementThe authors have declared no competing interest.