Targeting Multiple KRAS Mutations with High-Affinity Macrocyclic Inhibitors: From Discovery to Preclinical Validation

Area of Science:

• Oncology
• Medicinal Chemistry
• Molecular Biology

Background:

• Targeting KRAS mutations is crucial for cancer therapy.
• The discovery of RAS Switch-II pockets opened new avenues for drug development.
• Existing KRAS inhibitors primarily focus on the KRAS^G12C mutation.

Purpose of the Study:

• To develop novel inhibitors targeting KRAS^G12D and KRAS^G12V mutations.
• To identify potent compounds with high affinity for KRAS mutant proteins.
• To evaluate the efficacy of novel inhibitors in preclinical cancer models.

Main Methods:

• Utilized a macrocyclization strategy to design and synthesize potential drug candidates.
• Performed biochemical assays to assess compound affinity for KRAS^G12D and KRAS^G12V.
• Conducted cell-based assays to measure phospho-ERK inhibition in KRAS mutant cell lines.
• Evaluated tumor regression in mouse xenograft models treated with lead compounds.

Main Results:

• Identified an exceptionally potent lead compound (compound 12) through macrocyclization.
• Compound 12 demonstrated strong affinity for both KRAS^G12D and KRAS^G12V.
• Achieved potent inhibition of phospho-ERK signaling in various KRAS mutant cell lines.
• Observed significant tumor regression in mouse xenograft models, indicating in vivo efficacy.

Conclusions:

• The developed macrocyclic compound 12 is a highly potent inhibitor of KRAS^G12D and KRAS^G12V.
• Optimized interactions within the RAS Switch-II pocket contribute to the compound's strong efficacy.
• This research provides a promising therapeutic candidate for cancers harboring KRAS^G12D and KRAS^G12V mutations.