Fig. 2: Limited evolutionary divergence confers selectivity for KRAS.
From: Pan-KRAS inhibitor disables oncogenic signalling and tumour growth
a, RASless mouse embryonic fibroblasts expressing the indicated RAS isoforms were treated for 2 h. Cell extracts were subjected to RBD pull down and immunoblotting to determine the amount of active RAS. b, Sequence alignment of the G domain of RAS isoforms. c,d, Effect of isoform mimetic substitutions on RAS inhibition: RAS-GTP (c) and HRAS-GTP (d). HEK293 cells expressing the indicated mutants were treated for 2 h to determine the effect on RAS activation by using RBD pull down, immunoblotting and densitometry. e, Cocrystal structure of drug-bound KRAS showing H bonds between S122, N85 and K117 (black dotted lines, distance in Å). A representative of two independent experiments is shown in a, c and d.
