NMR in integrated biophysical drug discovery for RAS: past, present, and future.

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• RAS oncogenes, particularly KRAS, are frequently mutated in human cancers (~30%).
• Oncogenic RAS mutations lead to constitutive GTP-bound states, promoting uncontrolled cell proliferation.
• RAS proteins are challenging drug targets due to their lack of classic druggable pockets.

Purpose of the Study:

• To review the history and progress of RAS inhibitor development.
• To highlight the utility of Nuclear Magnetic Resonance (NMR) and integrated biophysical approaches in RAS drug discovery.
• To discuss various strategies for targeting RAS, including indirect inhibition and direct targeting of shallow pockets or the RAS-membrane interface.

Main Methods:

• Utilizing NMR for characterization and screening of RAS inhibitors.
• Employing integrated biophysical approaches to assess inhibitor binding and efficacy.
• Developing mutation-specific covalent inhibitors and peptidyl inhibitors.

Main Results:

• Discovery of molecules that bind RAS by stabilizing shallow pockets via conformational selection.
• Identification of strategies to enhance small molecule potency by targeting the RAS-membrane interface.
• Advancement of mutation-specific covalent inhibitors (e.g., targeting G12C) into clinical trials.

Conclusions:

• Significant progress has been made in developing direct RAS inhibitors, overcoming previous challenges.
• NMR and biophysical techniques are crucial for advancing RAS-targeted therapies.
• Future research holds promise for more effective cancer treatments by targeting RAS signaling pathways.