In rat and monkey studies, Larotrectinib (LOXO-101) demonstrates 33-100% oral bioavailability and 60-65% plasma protein binding. It has low brain penetration, and is well tolerated in 28 day (d) GLP toxicology studies. A single dose (30 mg/kg) of Larotrectinib (LOXO-101) reduces tyrosine phosphorylation of TRKA and downstream signal transduction (pERK) in the tumor >80%[1]. Athymic nude mice injected with KM12 cells are treated with Larotrectinib (LOXO-101) orally daily for 2 weeks. Dose-dependent tumor inhibition is observed demonstrating the ability of this selective compound to inhibit tumor growth in vivo[4]. Larotrectinib (LOXO-101) (200mg/kg/day p.o for six weeks) reduces leukemic infiltration to undetectable levels in the bone marrow and spleen compared to vehicle-treated mice. Mice treated with Larotrectinib (LOXO-101) are still alive and leukemia-free four weeks after the cessation of treatment, as determined by Xenogen imaging[5].
In Vitro
Larotrectinib (LOXO-101) is an ATP-competitive oral inhibitor of the tropomyosin-related kinase (TRK) family of receptor kinases (TRKA, B, and C), with low nanomolar 50% inhibitory concentrations against all three isoforms, and 1,000-fold or greater selectivity relative to other kinases[1][2]. Measurement of proliferation following treatment with Larotrectinib (LOXO-101) demonstrates a dose-dependent inhibition of cell proliferation in all three cell lines. The IC50 is less than 100 nM for CUTO-3.29 and less than 10 nM for KM12 and MO-91 consistent with the known potency of this drug for the TRK kinase family[3].
Kinase Assay
Cell Assay
Animal Administration
Mice[4] Athymic nude mice are used throughout the study. 5×105 KM12 cells are injected subcutaneously into the dorsal flank area of the mice. Tumor volume is monitored by direct measurement with calipers and calculated by the formula: length × (width2)/2. Following the establishment of tumor and when the tumor size is between 150-200 mm2, mice are randomly selected to receive diluent, 60 mg/kg/dose or 200 mg/kg/dose of Larotrectinib (LOXO-101). Larotrectinib (LOXO-101) is administered by oral gavage once daily for 14 days. After the last dose, tissue and blood are collected at 3, 6 and 24 hours post-treatment[4].
References
[1]. Karyn Bouhana, et al. LOXO-101, a pan TRK inhibitor, For The Treatment Of TRK-driven Cancers.
[2]. Nagasubramanian R, et al. Infantile Fibrosarcoma With NTRK3-ETV6 Fusion Successfully Treated With the Tropomyosin-Related Kinase Inhibitor LOXO-101. Pediatr Blood Cancer. 2016 Aug;63(8):1468-70.
[3]. Doebele RC, et al. An Oncogenic NTRK Fusion in a Patient with Soft-Tissue Sarcoma with Response to the Tropomyosin-Related Kinase Inhibitor LOXO-101. Cancer Discov. 2015 Oct;5(10):1049-57.
[4]. Doebele RC, et al. An Oncogenic NTRK Fusion in a Patient with Soft-Tissue Sarcoma with Response to the Tropomyosin-Related Kinase Inhibitor LOXO-101. Cancer Discov. 2015 Oct;5(10):1049-57.
[5]. Kathryn G, et al. Genetic Modeling and Therapeutic Targeting of ETV6-NTRK3 with Loxo-101in Acute Lymphoblastic Leukemia. Blood 2016 128:278.
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