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

Yujie Shao1,2, Kazuki Miura1,2, Hiroyuki Nakamura1,2

  • 1School of Life Science and Technology, Institute of Science Tokyo, 4259 Nagatsuta-cho Midori-ku, Yokohama 226-8501, Japan.

ACS Bio & Med Chem Au
|June 22, 2026
PubMed

Insights

Researchers developed novel carborane-based degraders (HY8) that selectively eliminate Kirsten rat sarcoma viral oncogene homologue (KRAS)G12C. This approach offers a new strategy for targeting oncogenic KRAS proteins and suppressing cancer signaling pathways.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • Persistent activation of KRASG12C mutations drives oncogenic signaling in various cancers.
  • Existing covalent inhibitors for KRASG12C may lead to incomplete pathway suppression or drug resistance.

Purpose of the Study:

  • To develop novel hydrophobic-tag (HyT) degraders for selective elimination of endogenous KRASG12C.
  • To investigate the mechanism of action and efficacy of carborane-HyT conjugates (HY8) against KRASG12C.

Main Methods:

  • Development of carborane-HyT conjugates (HY8) by incorporating a carborane cluster into an MRTX849 KRASG12C covalent ligand.
  • Assessment of KRASG12C abundance, ERK phosphorylation, and cytotoxicity in mutant cancer cells.
  • Mechanistic studies involving proteasome and lysosomal inhibitors, ubiquitination assays, and heat shock protein 70 engagement.

Main Results:

  • Carborane-HyT conjugates (HY8) effectively reduced KRASG12C abundance and ERK phosphorylation.
  • HY8 demonstrated lower intrinsic cytotoxicity compared to analogues, with equal or superior activity.
  • Degradation occurred via an E3 ligase-independent, chaperone-assisted, proteasome-dependent pathway, confirmed by resistance to lysosomal inhibition and rescue by proteasome inhibition.

Conclusions:

  • Carborane serves as a functional hydrophobic tag for driving proteasome-dependent degradation of endogenous KRASG12C.
  • This study broadens degrader design strategies to include E3-independent modalities for targeting oncogenic proteins.
  • The developed HY8 conjugates represent a promising therapeutic strategy for cancers driven by KRASG12C mutations.
Keywords:
Kirsten rat sarcoma viral oncogene homologue (KRAS)carboraneheat shock protein 70-mediated degradationhydrophobic tag (HyT)targeted protein degradation (TPD)

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