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Larotrectinib (LOXO-101) is an ATP-competitive oral, selective inhibitor of the tropomyosin-related kinase (TRK) family receptors, with low nanomolar 50% inhibitory concentrations against all three isoforms (TRKA, B, and C). TrkA TrkB TrkC

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].

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].

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