Inspired by one of nature’s solutions to modulating complex cellular targets, our platform enables chemical remodeling of chaperone proteins to inhibit frontier oncology targets through tri-complex formation. Our tri-complex inhibitors induce formation of novel druggable sites on classically featureless, undruggable surfaces. Using this approach, we have generated a series of RAS(ON) inhibitors that selectively target the active state of RAS for the first time.
Targeting RAS
RAS(ON) proteins were amongst the most notoriously undruggable targets in cancer. Our tri-complex inhibitor platform enables direct inhibition of the active, ON state of RAS driving formation of a novel tri-complex and blocking oncogenic signaling.
Using structure-guided design, we create molecules that bind to the chaperone protein cyclophilin A to form a novel interface with high affinity for RAS(ON) proteins. The resulting inhibitory tri-complexes can be tailored to bind to different RAS(ON) proteins, including those with oncogenic mutations at each of the three most commonly mutated hotspots – G12, G13 and Q61. For more information on the mechanism, read our recent publication in Science. To learn more about our development-stage inhibitors of oncogenic RAS, please visit our pipeline.
