Reversible Small Molecule Multivariant Ras Inhibitors Display Tunable Affinity for the Active and Inactive Forms of...

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Activating Ras mutations are key cancer drivers, frequently linked to poor prognoses.
• Current KRas G12C inhibitors address a specific mutation, leaving a significant unmet need for other Ras variants.
• The efficacy of targeting non-G12C Ras mutants remains largely unexplored.

Purpose of the Study:

• To discover novel reversible inhibitors targeting a broad spectrum of Ras mutations.
• To investigate inhibitors binding to an enlarged switch I-II pocket in Ras proteins.
• To evaluate the potential of these inhibitors in blocking Ras-driven signaling pathways.

Main Methods:

• Design and synthesis of a novel series of reversible Ras inhibitors.
• Biochemical assays to determine binding affinities and states (active/inactive) for inhibitors.
• Cellular assays to assess inhibition of Ras-Raf interaction and downstream ERK phosphorylation.

Main Results:

• Identified reversible inhibitors with nanomolar affinities for an enlarged Ras switch I-II pocket.
• Developed chemotypes that selectively bind inactive Ras, active Ras, or both states.
• Demonstrated that active-state binders inhibit wild-type Ras and multiple oncogenic KRas mutants, blocking Ras-Raf interaction and reducing ERK phosphorylation in cells.

Conclusions:

• A novel class of reversible Ras inhibitors targeting an enlarged pocket has been discovered.
• These inhibitors demonstrate broad activity against various Ras mutants, including non-G12C variants.
• The findings present a promising new strategy for developing multivariant Ras inhibitors to treat diverse cancers.