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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].

Table 15: 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

  1. 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.

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