Mechanism of Action
In cell-based phosphorylation assays, repotrectinib demonstrated high selectivity for wild-type and mutated TRKA, TRKB, TRKC, ROS1, and ALK proteins as measured by IC50 values [1].
Repotrectinib Inhibition of Kinase Activity [1]
Target |
IC50 (nmol/L) |
TRKA wild type |
0.533 |
TRKA G595R mutant |
2.67 |
TRKB wild type |
0.297 |
TRKB G639R mutant |
2.66 |
TRKC wild type |
0.211 |
TRKC G623R mutant |
4.46 |
ROS1 wild type |
0.071 |
ROS1 G2032R mutant |
0.456 |
ROS1 D2033N mutant |
0.236 |
ALK wild type |
1.04 |
ALK G1202R mutant |
1.21 |
Repotrectinib is selectively cytotoxic to engineered cell lines with ROS1, NTRK, or ALK gene rearrangements, without being cytotoxic to normal cells or cell lines with other oncogenic drivers [1]. In addition, repotrectinib has demonstrated tumour growth suppression in mutated TRKA, ROS1, and ALK protein (i.e., TRKA-G595R, ROS1-G2032R, and ALK-G1202R, respectively) mouse xenograft models as well as their wild-type equivalents [1].
References
- Drilon A, Ou SI, Cho BC et al. Repotrectinib (TPX-0005) Is a Next-Generation ROS1/TRK/ALK Inhibitor That Potently Inhibits ROS1/TRK/ALK Solvent- Front Mutations. Cancer Discov 2018; 8: 1227-1236.