A First-Class Degrader Candidate Targeting Both KRAS G12D and G12V Mediated by CANDDY Technology Independent of Ubiquitination.

ABSTRACT: "Undruggable" targets such as KRAS are particularly challenging in the development of drugs. We devised a novel chemical knockdown strategy, CANDDY (Chemical knockdown with Affinity aNd Degradation DYnamics) technology, which promotes protein degradation using small molecules (CANDDY molecules) that are conjugated to a degradation tag (CANDDY tag) modified from proteasome inhibitors. We demonstrated that CANDDY tags allowed for direct proteasomal target degradation independent of ubiquitination. We synthesized a KRAS-degrading CANDDY molecule, TUS-007, which induced degradation in KRAS mutants (G12D and G12V) and wild-type KRAS. We confirmed the tumor suppression effect of TUS-007 in subcutaneous xenograft models of human colon cells (KRAS G12V) with intraperitoneal administrations and in

SUBMITTER: Miyamoto-Sato E 

PROVIDER: S-EPMC10386196 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature