Discovery of a Bicyclic Peptidyl Pan-Ras Inhibitor

The Ras subfamily of small GTPases is mutated in similar to 30% of human cancers and represents compelling yet challenging anticancer drug targets owing to their flat protein surface. We previously reported a bicyclic peptidyl inhibitor, cyclorasin B3, which binds selectively to Ras-GTP with modest affinity and blocks its interaction with downstream effector proteins in vitro but lacks cell permeability or biological activity. In this study, optimization of B3 yielded a potent pan-Ras inhibitor, cyclorasin B4-27, which binds selectively to the GTP-bound forms of wildtype and mutant Ras isoforms (K-D = 21 nM for KRasG12V-GppNHp) and is highly cell-permeable and metabolically stable (serum t(1/2) > 24 h). B4-27 inhibits Ras signaling in vitro and in vivo by blocking Ras from interacting with downstream effector proteins and induces apoptosis of Ras-mutant cancer cells. When administered systemically (i.v.), B4-27 suppressed tumor growth in two different mouse xenograft models at 1-5 mg/kg of daily doses.

Automated summary

The study introduces a novel pan-Ras inhibitor, cyclorasin B4-27, with strong cell permeability and metabolic stability, which effectively inhibits Ras signaling both in vitro and in vivo by blocking Ras interaction with downstream effector proteins and inducing apoptosis in Ras-mutant cancer cells.