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

Activating mutations of Ras are one of the most prevalent drivers of cancer and are often associated with poor clinical outcomes. Despite FDA approval for two irreversible inhibitors that target the inactive state of KRas^G12C, significant unmet clinical need still exists, and the susceptibility of non-G12C mutants to inactive-state inhibition remains unclear. Here we report the discovery of a novel series of reversible inhibitors that bind in an enlarged version of the switch I-II pocket with nanomolar affinities. Dependent on chemotype these can either preferentially bind to the inactive or active state or bind both with similar affinity. The active-state binders inhibit the Raf interaction for wild-type Ras, and a broad range of oncogenic KRas mutants with nanomolar potency. A subseries of these molecules displays cellular inhibition of Ras-Raf binding, as well as decreased phosphorylation of the downstream protein ERK, demonstrating that potent multivariant Ras inhibitors can be accessed from this novel pocket.