target/Ras/1

(2Z,3Z)-U0126 is a highly selective inhibitor of both MEK1 and MEK2, a type of MAPK ERK kinase. It was found to functionally antagonize AP-1 transcriptional activity via noncompetitive inhibition of the dual specificity kinase MEK with IC50 of 72 nM for MEK1 and 58 nM for MEK2. U0126 inhibited anchorage-independent growth of Ki-ras-transformed rat fibroblasts by simultaneously blocking both extracellular signal-regulated kinase and mammalian target of rapamycin pathways.

BBO-8520 is a first-in-class, direct dual inhibitor of both the active (ON) and inactive (OFF) conformational states of KRASG12C. BBO-8520 binds to the Switch-II/Helix3 pocket of KRASG12C, covalently modifying the target cysteine residue and thereby disabling effector binding in the ON state. BBO-8520 exhibits potent inhibition of KRAS signaling under growth factor-activated conditions, where existing OFF-only inhibitors demonstrate minimal activity. In vivo, BBO-8520 rapidly engages its target and suppresses signaling, resulting in durable tumor regression across multiple models, including those resistant to OFF-only KRASG12C inhibitors.