Therapeutic Targeting the Allosteric Cysteinome of RAS and Kinase Families

•Allosteric inhibitors have many theoretical advantages including superior selectivity, the ability to modulate allosteric biological processes, and the ability to fine-tune biological responses.•Allosteric KRAS G12C inhibitor development showed that covalent chemistry can convert a suboptimal binding pocket into a druggable pocket.•In this review, we review the broader history of allosteric inhibitor development in the RAS and kinase fields and identify opportunities to accelerate allosteric drug development by leveraging covalent chemistry targeting cysteines.