Carborane Hydrophobic Tags Drive Selective Degradation of Endogenous KRASG12C via HSP70-Ubiquitin-Proteasome Pathway.

Persistent activation of the Kirsten rat sarcoma viral oncogene homologue (KRAS)G12C mutation sustains oncogenic signaling, and covalent inhibitors often yield incomplete pathway suppression or resistance. Herein, we developed hydrophobic-tag (HyT) degraders by introducing a carborane cluster into MRTX849, an KRASG12C covalent ligand, to promote selective elimination of endogenous KRASG12C. The carborane-HyT conjugates (HY8) reduced KRASG12C abundance and ERK phosphorylation in mutant cancer cells while showing lower intrinsic cytotoxicity and activity equal or superior to the adamantane-HyT analogue (HY5). Mechanistic studies indicate that HY8 acts in an E3 ligase-independent, chaperone-assisted pathway. KRAS degradation was rescued by the proteasome inhibitor MG132, but not by the lysosomal inhibitor bafilomycin A1, consistent with the increased level of KRAS ubiquitination and heat shock protein 70 engagement. Competition with MRTX849 blocked KRAS degradation, supporting on-target covalent engagement at Cys12. These findings establish carborane as a compact, functional HyT that drives proteasome-dependent degradation of endogenous KRASG12C and suppresses downstream signaling, broadening degrader design to include an E3-independent modality for the degradation of oncogenic proteins.