Drugging an undruggable pocket on KRAS

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• RAS proteins (KRAS, NRAS, HRAS) are small GTPases crucial for cell signaling.
• Activating RAS mutations are common oncogenic drivers in human cancers, particularly KRAS.
• Despite KRAS being a key drug target, no direct RAS-targeting therapeutics are approved.

Purpose of the Study:

• To discover and characterize novel inhibitors targeting the KRAS protein.
• To validate the druggability of the switch I/II pocket in KRAS.
• To develop a chemical probe for targeting both active and inactive forms of KRAS.

Main Methods:

• Structure-based drug design was employed to identify BI-2852.
• BI-2852's binding affinity and mechanism of action were assessed.
• Antiproliferative effects were evaluated in KRAS-mutant cancer cells.

Main Results:

• BI-2852 (1) demonstrated nanomolar binding affinity to a previously inaccessible switch I/II pocket on RAS.
• The inhibitor is mechanistically distinct from covalent KRAS^G12C inhibitors, targeting both active and inactive RAS forms.
• BI-2852 inhibited downstream signaling and exhibited antiproliferative effects in KRAS-mutant cells.

Conclusions:

• The switch I/II pocket on RAS is druggable.
• BI-2852 represents a novel chemical probe for targeting both active and inactive RAS.
• This discovery opens new avenues for therapeutic development against KRAS-driven cancers.