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. Author manuscript; available in PMC: 2022 Dec 20.
Published in final edited form as: Nat Cancer. 2022 Jun 20;3(6):710–722. doi: 10.1038/s43018-022-00399-6

Figure 3. Selectivity of LA7 and LA9 against I1171N and G1202R single and compound mutants, respectively.

Figure 3.

(A) Relative selectivity of LA7 and LA9 for single ALK mutants, calculated by the ratio IC50(LA7)/IC50(LA9). (B)-(C) Comparison of relative fold increase in potency of LA7 vs LA9 (over lorlatinib) against single and compound ALK mutants. LA9 has a greater increase in potency relative to lorlatinib against G1202R single and compound mutations compared to LA7 (B). Conversely, LA7 has greater increase in potency relative to lorlatinib against I1171N single and compound mutations compared to LA9 (C). (D) Selectivity of LA7 and LA9 against Ba/F3 models harboring G1202R (G1202R+L1198F, G1202R+L1196M, G1202R+S1206F, G1202R+G1269A, G1202R+S1206F+G1269A), I1171N/S (I1171S+L1198F, I1171N+L1198F, I1171N+D1203N, I1171N+C1156Y, I1171S+C1156Y), or other compound ALK mutations (F1174C+D1203N, D1203N+E1210K, C1156Y+L1198F, F1174C+L1198F, L1196M+L1198F, L1198F+G1269A) calculated by the ratio IC50(LA7)/IC50(LA9). Circles indicate clinical mutations, and diamonds indicate putative mutations. (E) Western blot analysis performed in Ba/F3 cells expressing ALK G1202R+L1196M or ALK I1171N+D1203N after treatment with DMSO, LA7, LA9, or lorlatinib for 6 hours. The images shown are representative of at least two repeats with similar results.