Oops, you're using an old version of your browser so some of the features on this page may not be displaying properly.

MINIMAL Requirements: Google Chrome 24+Mozilla Firefox 20+Internet Explorer 11Opera 15–18Apple Safari 7SeaMonkey 2.15-2.23

Previous Page Next Page

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]


Larotrectinib IC50 (nmol/L)

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

TRKA wild type



 TRKA G595R mutant



 TRKA G667C mutant



TRKC wild type



 TRKC G623R mutant



 TRKC G696A mutant



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]. 


  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.

This site uses cookies. Some of these cookies are essential, while others help us improve your experience by providing insights into how the site is being used.

For more detailed information on the cookies we use, please check our Privacy Policy.

Customise settings