LOXO-195 is a new-generation and selective TRK inhibitor with IC50 values of 0.6nM, 2nM, 9.8nM, <2.5nM, 2.3nM and <2.5nM for TrkAWT, TrkAG595R, TrkAG667C, TrkCWT, TrkCG623R and TrkCG696A, respectively. Consistent with this, LOXO-195 displayed potent inhibitory effect on p-TRK in NIH-3T3 cells expressing TRK kinase acquired resistance mutations (IC50 1.6-64nM), with decrease p-ERK level (IC50 2-45nM) observed. Oral administration of LOXO-195 at dose of 30mg/kg, 100mg/kg and 300mg/kg, BID, led a dose-dependent tumor growth inhibition of mice xenograft these NIH-3T3 cells expressing different TRK resistance mutations. Distinguished from the other Trk inhibitor like larotrectinib, LOXO-195 abrogated resistance in TRK fusion–positive cancers that acquired kinase domain mutations, a shared liability with all existing TRK TKIs[1].
作用机制
The specific structure of LOXO-195 with ability to accommodate the bulky, positively charged arginine side chain in the solvent front without any steric clashes distinguishes it from the other Trk inhibitor like larotrectinib.[1]
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