Fig. 1: In vitro efficacy and structural basis of binding of larotrectinib and altiratinib for NTRK fusion proteins. | Communications Biology

Fig. 1: In vitro efficacy and structural basis of binding of larotrectinib and altiratinib for NTRK fusion proteins.

From: NTRK kinase ___domain mutations in cancer variably impact sensitivity to type I and type II inhibitors

Fig. 1

Chemical structures of larotrectinib (a), and altiratinib (b). Dose-response cell viability of onco-addicted Ba/F3 TPM3-NTRK1 (c) or ETV6-NTRK3 fusion (d) expressing cells after treatment with larotrectinib or altiratinib for 72 h. Representative data are average ± standard error of means (SEM) from three independent replicates. e, f Immunoblot analysis of TPM3-NTRK1 and ETV6-NTRK3 autophosphorylation (pNTRK), as well as Erk1/2 phosphorylation (pErk1/2), corresponding total NTRK (tNTRK) and Erk1/2 (tErk1/2) levels, and loading control (Gapdh). “Veh.” indicates vehicle (dimethyl sulfoxide (DMSO)) treatment. Data are representative of four independent experiments. Structural homology models of NTRK1 in DFG-in (type I) or DFG-out (type II) conformations bound to larotrectinib (g) or altiratinib (h); type I and type II are the favored binding modes for larotrectinib and altiratinib, respectively.

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