LOXO-195 is a new-generation and selective TRK inhibitor with IC50 values of 0.6nM, 2nM, 9.8nM, <2.5nM, 2.3nM and <2.5nM for TrkAWT, TrkAG595R, TrkAG667C, TrkCWT, TrkCG623R and TrkCG696A, respectively. Consistent with this, LOXO-195 displayed potent inhibitory effect on p-TRK in NIH-3T3 cells expressing TRK kinase acquired resistance mutations (IC50 1.6-64nM), with decrease p-ERK level (IC50 2-45nM) observed. Oral administration of LOXO-195 at dose of 30mg/kg, 100mg/kg and 300mg/kg, BID, led a dose-dependent tumor growth inhibition of mice xenograft these NIH-3T3 cells expressing different TRK resistance mutations. Distinguished from the other Trk inhibitor like larotrectinib, LOXO-195 abrogated resistance in TRK fusion–positive cancers that acquired kinase domain mutations, a shared liability with all existing TRK TKIs[1].
作用机制
The specific structure of LOXO-195 with ability to accommodate the bulky, positively charged arginine side chain in the solvent front without any steric clashes distinguishes it from the other Trk inhibitor like larotrectinib.[1]
Selitrectinib 细胞实验
Cell Line
Concentration
Treated Time
Description
References
KM12 colon cancer cells
0.001、0.01、0.1、1 、10 μM
Drugs and cell viability assay
Cancer Med. 2024 Jun;13(12):e7393.
IRC and KM12 cells
1-5000 nM
72 hours
To assess the effect of Selpercatinib on the growth inhibition and TRK-mediated signaling in NTRK fusion-positive tumor cells. Results showed that Selpercatinib significantly inhibited tumor cell growth and TRK signaling.
Br J Cancer. 2024 Aug;131(3):601-610.
IRC and KM12 cells
1-5000 nM
72 hours
To assess the effect of Selpercatinib on the growth inhibition and TRK-mediated signaling in NTRK fusion-positive tumor cells. Results showed that Selpercatinib significantly inhibited tumor cell growth and TRK signaling.
Br J Cancer. 2024 Aug;131(3):601-610.
Ba/F3 (LMNA-NTRK1, TRKA G595R)
100 nM
30 min
To test the inhibitory effect of Selitrectinib on TRKA G595R mutant cells, results showed inhibition on this mutation.
Br J Cancer. 2024 Aug;131(3):601-610.
Kor1 (TPM3-NTRK1)
100 nM
30 min
To test the inhibitory effect of Selitrectinib on NTRK fusion-positive cells, results showed inhibition on Kor1 cells.
Br J Cancer. 2024 Aug;131(3):601-610.
IRC (LMNA-NTRK1)
100 nM
30 min
To test the inhibitory effect of Selitrectinib on NTRK fusion-positive cells, results showed inhibition on IRC cells.
Br J Cancer. 2024 Aug;131(3):601-610.
NIH3T3 cells
18.7–341 nmol/L
72 hours
Evaluate the inhibitory effect of Selitrectinib on TRKA/B/C resistance mutations, showing moderate inhibitory activity against solvent-front (SFM) and xDFG mutations
Mol Cancer Ther. 2021 Dec;20(12):2446-2456.
Ba/F3 cells
1.8–3.9 nmol/L
72 hours
Evaluate the inhibitory effect of Selitrectinib on wild-type TRKA/B/C fusion proteins, showing moderate inhibitory activity
Mol Cancer Ther. 2021 Dec;20(12):2446-2456.
Selitrectinib 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
BALB/c nude female mice
KM12 (TPM3-NTRK1) xenografts
Oral
30 mg/kg BID
Twice daily for 10 days
To test the inhibitory effect of Selitrectinib in vivo on NTRK fusion-positive tumors, results showed inhibition on KM12 model.
Br J Cancer. 2024 Aug;131(3):601-610.
Nude mice
Patient-derived xenograft (PDX) model
Oral
100 mg twice daily, escalated to 150 mg twice daily, and finally to 200 mg twice daily
Twice daily for over 5 months
To evaluate the efficacy of Selitrectinib in metastatic undifferentiated sarcoma harboring NTRK1 G595R solvent-front mutation. Results showed a partial response with reduced fluorodeoxyglucose uptake and slow disease progression, with increased plasma drug levels upon dose escalation.
JCO Precis Oncol. 2020;4:79-90
Nude mice
NIH3T3 LMNA–TRKAG595R xenograft model
Oral
30 mg/kg
Twice daily, continuous treatment
Evaluate the inhibitory effect of Selitrectinib on TRKA G595R mutant tumors, showing 80% tumor growth inhibition
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