Larotrectinib (LOXO-101) is an ATP-competitive oral inhibitor targeting the tropomyosin-related kinase (TRK) family of receptor kinases (TRKA, B, and C). It exhibits low nanomolar 50% inhibitory concentrations against all three isoforms and demonstrates 1,000-fold or greater selectivity relative to other kinases[1][2]. Assessment of cell proliferation post-treatment with Larotrectinib (LOXO-101) reveals a dose-dependent suppression across all three cell lines. The IC50 values are below 100 nM for CUTO-3.29 and below 10 nM for KM12 and MO-91, aligning with the established potency of this drug against the TRK kinase family[3].
体内研究
In rat and monkey models, Larotrectinib (LOXO-101) exhibits oral bioavailability ranging from 33% to 100% and plasma protein binding between 60% and 65%. It displays minimal brain penetration and demonstrates good tolerance in 28-day GLP toxicology assessments. A single administration of Larotrectinib (LOXO-101) at a dose of 30 mg/kg reduces tyrosine phosphorylation of TRKA and downstream signal transduction (pERK) in tumors by over 80%[1].
Athymic nude mice inoculated with KM12 cells receive daily oral doses of Larotrectinib (LOXO-101) for two weeks. The treatment results in dose-dependent inhibition of tumor growth, indicating the efficacy of this selective compound in suppressing tumor growth in vivo[4].
Larotrectinib (LOXO-101) (200mg/kg/day, pO for six weeks) leads to the elimination of leukemic infiltration in the bone marrow and spleen, compared to mice treated with the vehicle alone. Even four weeks after the treatment is stopped, mice receiving Larotrectinib (LOXO-101) remain alive and free from leukemia, as confirmed by Xenogen imaging[5].
体外研究
Larotrectinib (LOXO-101) is an ATP-competitive oral inhibitor targeting the tropomyosin-related kinase (TRK) family of receptor kinases (TRKA, B, and C). It exhibits low nanomolar 50% inhibitory concentrations against all three isoforms and demonstrates 1,000-fold or greater selectivity relative to other kinases[1][2].
Assessment of cell proliferation post-treatment with Larotrectinib (LOXO-101) reveals a dose-dependent suppression across all three cell lines. The IC50 values are below 100 nM for CUTO-3.29 and below 10 nM for KM12 and MO-91, aligning with the established potency of this drug against the TRK kinase family[3].
Larotrectinib/拉罗替尼 细胞实验
Cell Line
Concentration
Treated Time
Description
References
143B/NGF cells
10-100 µM
24 or 48 hours
To evaluate the effect of Larotrectinib on the viability of 143B/NGF cells, results showed that Larotrectinib had no cytotoxic effects on the cells
Int J Biol Sci. 2024 Aug 1;20(11):4114-4127.
BaF3/RET(D898_E901del)/ETV6::NTRK3 cells
100 nM
3 days
To validate the efficacy of selpercatinib in combination with larotrectinib or entrectinib on cells containing both RET and NTRK3 oncogenes. Results showed that the combination of selpercatinib with larotrectinib or entrectinib significantly reduced the IC50 values to 10 nM and 1.8 nM, respectively.
To validate the efficacy of selpercatinib in combination with larotrectinib or entrectinib on cells containing RET, NTRK3, and ALK oncogenes. Results showed that the combination of selpercatinib with entrectinib had the lowest IC50 value (14.19 nM) and could completely suppress these cells at 75 nM.
NPJ Precis Oncol. 2024 Mar 4;8(1):62.
NthyTPR-NTRK cells
50 µM
Larotrectinib restored 125I uptake in NthyTPR-NTRK cells, mediated by the NIS.
J Clin Invest. 2021 Sep 15;131(18):e144847.
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.
Larotrectinib/拉罗替尼 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mice
Wild-type and genetically modified mice
Oral
10 mg/kg
Single dose, lasting 1 hour or 8 hours
To investigate the effects of ABCB1 and ABCG2 on the oral bioavailability and tissue distribution of Larotrectinib, results showed that ABCB1 and ABCG2 significantly limited the oral bioavailability and brain accumulation of Larotrectinib
Br J Pharmacol. 2020 Jul;177(13):3060-3074.
Nude mice (BALB/c)
HCT116 xenograft model
Intragastric administration
20 mg/kg
Twice daily for 3 weeks
Lar significantly suppressed tumour volume and weight in the HCT116 xenograft model and activated autophagy through the AMPK/mTOR signalling pathway.
J Cell Mol Med. 2022 Nov;26(21):5539-5550.
C57BL/6 mice
B16 melanoma model
Oral
200 mg/kg
Once daily for 60 days
Larotrectinib combined with immunotherapy significantly increased the complete remission rate of melanoma and achieved durable cure
Nat Immunol. 2024 Feb;25(2):268-281.
SCID mice
Prostate cancer xenograft model
Subcutaneous injection
300 mg/kg
Every 24 hours for 28 days
Larotrectinib combined with ML210 significantly inhibited tumor growth
J Exp Clin Cancer Res. 2024 Jan 11;43(1):16.
Nude mice
Osteosarcoma xenograft model
Oral
50 mg/kg
Three times a week for four weeks
To evaluate the effect of Larotrectinib on NGF-mediated tumor growth, results showed that Larotrectinib significantly inhibited tumor growth
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