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Mechanism of Action

BAY 2731954 (LOXO-195) selectively targets NTRK 1/2/3 gene fusions [1], and is being developed for its ability to overcome acquired resistance to first-generation TRK protein kinase inhibitors mediated by recurrent mutations to the kinase domain (i.e. solvent-front mutations, and xDFG substitutions) [1]. The kinase solvent-front mutation is mediated through G595R in the TRKA protein and G623R in the TRKC protein, while the xDFG motif is found at G667C in the TRKA and G696A in the TRKC proteins.

Inhibitory activity as measured by IC50 values was similar to larotrectinib for wild-type kinase domains, but BAY 2731954 (LOXO-195) achieved much lower nanomolar inhibitory activity against mutated domain kinase activity [1].

Table 13: BAY 2731954 (LOXO-195) Inhibition of Kinase Activity [1]

Target

Larotrectinib IC50 (nmol/L)

BAY 2731954 (LOXO-195) IC50 (nmol/L)

TRKA wild type

0.9

0.6

 TRKA G595R mutant

69.0

2.0

 TRKA G667C mutant

45.5

9.8

TRKC wild type

2.8

<2.5

 TRKC G623R mutant

48.0

2.3

 TRKC G696A mutant

4.5

<2.5

LOXO-195 is also selectively cytotoxic to cell lines containing TRK fusion proteins (see the figure below) [1, 2].

Figure 8: Inhibition of Proliferation by BAY 2731954 (LOXO-195) [2]

Figure 8: Inhibition of Proliferation by BAY 2731954 (LOXO-195)

Each cell line was treated with 10 concentrations of BAY 2731954 (LOXO-195) in triplicate for 72 hours, followed by DAPI staining and cell counting.
With permission from Blake et al. [2].

In addition, BAY 2731954 (LOXO-195) shows inhibitory activity in cells across all resistance mutations previously identified preclinically and in patients [1].

Consistent with IC50 findings, BAY 2731954 (LOXO-195) inhibited tumour growth in both mice transfected with wild-type and mutated TRK protein (NIH 3T3 ΔTRKA and TRKA G595R, respectively [1]. 

References

  1. Drilon A, Nagasubramanian R, Blake JF et al. A Next-Generation TRK Kinase Inhibitor Overcomes Acquired Resistance to Prior TRK Kinase Inhibition in Patients with TRK Fusion-Positive Solid Tumors. Cancer Discov 2017; 7: 963-972.
  2. Blake J, Kolakowski GR, Tuch B et al. The development of LOXO-195, a second generation TRK kinase inhibitor that overcomes acquired resistance to 1st generation inhibitors observed in patients with TRK-fusion cancers. European Journal of Cancer 2016; 69: S144-S145.

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