Mechanism of Action
In biochemical phosphorylation assays, taletrectinib potently inhibits recombinant NTRK1, NTRK3 and ROS1, in sub-nanomolar concentration in an ATP-competitive manner. Furthermore, in vitro it has been shown to be highly active against cell carrying NTRK1-rearrangements and in in vivo experiments using the KM12-bearing mouse xenograft model, which harbors TPM3-NTRK1 fusion gene, taletrectinib induced dose-dependent tumor shrinkage without significant body weight loss [1].
Taletrectinib Inhibition of NTRK Kinase Activity [1]
Kinase |
IC50 (nM) |
|
|
ATP (Km) |
ATP (1mM) |
NTRK1 |
0.622 |
3.01 |
NTRK2 |
2.28 |
9.52 |
NTRK3 |
0.980 |
9.28 |
ROS |
0.207 |
0.898 |
Taletrectinib Inhibition of NTRK1 mutants [1]
Ba/F3 line |
IC50 (nM) |
WT |
1.88 |
L564H |
25.8 |
G595R |
85.6 |
G595L |
29.2 |
F646I |
25.6 |
D679G |
1.8 |
G667C |
304.1 |
Parental (+IL3) |
>1000 |
References
- Katayama R, Gong B, Togashi N et al. The new-generation selective ROS1/NTRK inhibitor DS-6051b overcomes crizotinib resistant ROS1-G2032R mutation in preclinical models. Nat Commun. 2019;10(1):3604.