Extended Data Fig. 10. Structural basis for selectivity of lorlatinib analogs against ALK compound mutations and the L1198F mutation.

(A) Energy-minimized model of LA9 bound to G1202R/L1196M. Solvent front G1202R and D1203 residues are bolded for emphasis. Productive interactions shown by dotted lines are similar to G1202R single mutant (see Fig. 7B). (B) Co-crystal structure of LA7 bound to wild-type ALK (upper) and energy minimized models of LA7 bound to I1171N (middle) and I1171N/D1203N (bottom) superimposed with energy-minimized model of I1171N (ligand and protein colored pink) showing that the network of hydrogen bonds between thiazole ring hydroxyl groups and solvent front residues are largely preserved. (C) Energy minimized model of LA7 bound to G1202R/L1196M showing disruption of solvent front hydrogen bond network, similar to G1202R single mutant (see Fig. 7D). (D)-(G) The L1198F mutation was modeled onto co-crystal structures of lorlatinib (D), LA7 (E), LA9 (F) or LA4 (G) bound to WT ALK. The L1198F substitution results in steric clash with the selectivity nitrile of lorlatinib. LA7 and LA9 lack the selectivity nitrile and can easily accommodate the L1198F substitution, whereas the nitrile of LA4 is positioned toward L1198F but exhibits reduced steric clash compared to lorlatinib due to the more flexible ligand structure. (H) Relative fold potency decrease of LA4 compared with LA7 (calculated by dividing the cellular IC50 values of LA4 by the that of LA7) against Ba/F3 models harboring compound ALK mutants. IC50 values correspond to data shown in the Source Data. (I) Superimposition of LA7 onto the LA4/L1198F model shown in Panel G comparing the position of the corresponding thiazole methyl or nitrile groups near L1198F.