Sequence-defined phosphoestamers for selective inhibition of the KRAS^G12D/RAF1 interaction

Area of Science:

• Medicinal Chemistry
• Oncology
• Molecular Biology

Background:

• RAS proteins are frequently mutated in various cancers, posing significant therapeutic challenges due to their role in protein-protein interactions (PPIs).
• Targeting the interaction surfaces of RAS proteins with downstream effectors has been a major hurdle in drug discovery.

Purpose of the Study:

• To develop a novel chemical platform, phosphoestamers, for targeting protein-protein interactions (PPIs).
• To identify inhibitors of the KRAS G12D-RAF interaction, a key pathway in cancer proliferation.

Main Methods:

• Adaptation of phosphoramidite chemistry for synthesizing a library of nearly one million non-nucleosidic oligophosphoester sequences (phosphoestamers).
• Utilized fluorescent-activated bead sorting (FABS) to screen for phosphoestamers inhibiting KRAS G12D-RAF interaction.
• Employed tandem mass spectrometry and orthogonal validation for hit identification and IC50 determination.

Main Results:

• Identified potent phosphoestamer inhibitors of KRAS G12D with IC50 values as low as 25 nM.
• Demonstrated excellent selectivity of the identified inhibitors for the mutant KRAS G12D over wild-type RAS.
• Validated the efficacy of phosphoestamers in inhibiting the KRAS G12D-RAF interaction.

Conclusions:

• Phosphoestamers represent a promising new chemical platform for targeting challenging protein-protein interactions (PPIs).
• This approach offers a potential new avenue for developing drugs against mutant RAS-driven cancers.
• The platform has broader implications for targeting PPIs in other diseases, including neurodegenerative disorders and viral infections.