Brønsted-basic small molecules activate GTP hydrolysis in KRAS-Q61 mutants

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• RAS oncogenes (KRAS, HRAS, NRAS) are frequently mutated in human cancers.
• Current therapies primarily target KRAS codon 12 mutations, leaving KRAS Q61 variants largely untreatable.
• RAS G12 and Q61 mutants exhibit impaired GTP hydrolysis, leading to sustained signaling.

Purpose of the Study:

• To develop novel therapeutic strategies targeting KRAS Q61 mutations.
• To identify small molecules that can restore GTPase activity to mutant RAS proteins.
• To explore a new paradigm for targeting RAS-driven cancers.

Main Methods:

• Screening for small molecules that accelerate GTP hydrolysis in KRAS-Q61 mutants.
• Characterizing the mechanism of action of identified compounds.
• Assessing the efficacy of compounds in mutant cancer cell lines.

Main Results:

• Discovery of small molecules that act as GTPase activators for KRAS-Q61 mutants.
• Compounds selectively enhance GTP hydrolysis by up to 20-fold in KRAS-Q61X mutants.
• Treatment with these compounds reduces GTP-bound RAS levels and downstream signaling in cancer cells.

Conclusions:

• Small-molecule GTPase activators represent a promising therapeutic strategy for KRAS-Q61 driven cancers.
• This work provides a mechanistic basis for targeting RAS mutations via GTP hydrolysis.
• Offers a new paradigm for developing treatments for previously intractable RAS-driven malignancies.