Selitrectinib (LOXO-195)

Information Selitrectinib (LOXO-195, BAY 2731954) is an orally available, highly potent, and selectiveTRK kinaseinhibitor with low nanomolar inhibitory activity against TRKA G595R, TRKC G623R, and TRKA G667C, IC50s ranging from 2.0 to 9.8 nmol/L. It is more than 1,000-fold selective for 98% of non-TRK kinases tested. Targets WT TRKA (Celll-free assay); TRKA G595R (Cell-free assay); TRKC G623R (Cell-free assay); WT TRKC (Cell-free assay); TRKC G696A (Cell-free assay) 31637,0.6 nM; 2 nM; 2.3 nM; 2.5 nM; 2.5 nM In vitro LOXO-195 potently inhibits diverse activated TRK kinases in vitro. At a concerntration of 1 μM, which is approximately 1,667-fold higher than its IC50 for TRKA (0.6 nmol/L), LOXO-195 is more than 1,000-fold selective for 98% of non-TRK kinases tested (228 individual kinases). LOXO-195 demonstrates potent inhibition of cell proliferation in TRK fusion–containing KM12, CUTO-3, and MO-91 cell lines (IC50 ≤ 5 nmol/L). In contrast, LOXO-195 treatment with concentrations up to 10 μmol/L has no inhibitory effect on the growth of the 84 cell lines that did not contain a TRK fusion. In vivo LOXO-195 is effective at reducing phosphorylated TRKA in tumors driven by ΔTRKA. LOXO-195 also causes inhibition of tumor growth relative to vehicle at all doses in four TRKA-dependent tumor models (NIH 3T3 ΔTRKA, ΔTRKA G595R, ΔTRKA G667C, and TPM3-NTRK1 fusion-positive KM12 colorectal cancer cells).

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