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. 2022 May 9;13:2530. doi: 10.1038/s41467-022-30258-y

Fig. 5. Inhibitor features and role of F723 in cooperative binding and synergy.

Fig. 5

a Pulldown of EGFR protein from HEK293T/17 cells transiently expressing EGFR(L858R/T790M) or EGFR(L858R/T790M/F723A) using b-JBJ-125 following treatment with different irreversible TKIs. F723A decreased the ability of select TKIs to enhance pulldown using b-JBJ-125 (n = 3 independent experiments). b Cooperative binding was not observed in the F723A variant in an FP binding assay using BODIPY-JBJ. Data are reported as mean (n = 2 independent experiments) EGFR(L858R/T790M) data are repeated from Fig. 2e for comparison. c Inhibition synergy resulted in a 20-fold increase in potency for JBJ-125 in the presence of osimertinib compared to approximately 2-fold in the L858R/T790M/F723A variant (top). Similarly, only a 3-fold increase in osimertinib potency was observed in the F723A variant compared to a 7.5-fold increase in L858R/T790M (bottom). Data are reported as mean ± SD (n = 3 independent experiments). Source data are provided as a Source Data file.