LAUSR

KRASG12C(ON) inhibitors with agents targeting pathway nodes both upand downstream of RAS, as well as other parallel pathways, can drive combination benefit in distinct cancer histotypes. Tri-complex inhibitors that target the active, GTP-bound form of KRAS thus represent a second generation of KRASG12C inhibitor. Chemical modulation of the noncovalent and covalent interactions of our tri-complex inhibitors provides an exciting opportunity to step beyond KRASG12C to target the GTP-bound state of additional RAS variants, and we demonstrate in vitro covalent inhibition of KRASG13C.