Targeting cancer with small-molecule pan-KRAS degraders

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Mutations in Kirsten rat sarcoma viral oncogene homolog (KRAS) are common drivers of cancer.
• Targeting oncogenic KRAS has been challenging, with current therapies limited to specific mutations like KRAS G12C using covalent inhibitors.

Purpose of the Study:

• To design and evaluate a novel heterobifunctional small molecule for the degradation of prevalent oncogenic KRAS alleles.
• To compare the efficacy of KRAS degradation versus inhibition in cancer models.

Main Methods:

• Biophysical and structural studies of KRAS ternary complexes.
• Design and synthesis of a heterobifunctional small molecule.
• Assessment of KRAS degradation in KRAS mutant cancer cell lines.
• Evaluation of pathway modulation and anti-cancer activity in vitro and in vivo.

Main Results:

• The designed small molecule potently degraded 13 out of 17 prevalent oncogenic KRAS alleles.
• KRAS degradation led to more profound and sustained pathway modulation compared to inhibition.
• Degradation selectively killed cancer cells with KRAS aberrations and was tolerated in vivo, causing tumor regression.

Conclusions:

• Small-molecule-mediated degradation of oncogenic KRAS represents a promising new therapeutic approach.
• This strategy offers a broader applicability across various KRAS mutations beyond KRAS G12C.
• The findings open a new avenue for treating KRAS-driven cancers.