Larotrectinib

Larotrectinib (VITRAKVIR) is an orally administered, small molecule, highly-selective, tropomyosin receptor kinase (TRK) inhibitor that was developed by Loxo Oncology in collaboration with Bayer AG as a treatment for adult and paediatric patients whose cancers harbour neurotrophic receptor tyrosine kinase (NTRK) gene fusions.Larotrectinib is a highly selective, potent inhibitor of TRKA, TRKB and TRKC (in vitro 50% inhibitory constant 5–11 nmol/L), with minimal or no activity against other kinase and non-kinase targets [1, 2]. Inhibition of TRKs prevents TRK activation, resulting in both the induction of cellular apoptosis and the inhibition of cell growth in tumours that overexpress TRKs.
LOXO-101 is an inhibitor of the tropomyosin-related kinases TrkA, TrkB, and TrkC (IC50s = 2-20 nM). It is selective for TrkA, -B, and -C over a panel of 226 kinases at 1 μM. LOXO-101 inhibits the growth of CUTO-3.29, KM12, and MO-91 patient-derived cancer cell lines (IC50s = <100, <10, and <10 nM, respectively).In vivo, LOXO-101 (60 and 200 mg/kg) reduces tumor growth in a KM12 mouse xenograft model.
Larotrectinib, also known as LOXO-101 and ARRY-470, is a small molecule that was designed to block the ATP-binding site of the TRKA, TRKB, and TRKC, serving as a highly specific and potent inhibitor of all of the three tropomyosin kinase receptors.
Class: receptor tyrosine kinase; Treatment: NTRK-altered solid tumors; Other name: ARRY-407, LOXO-101; Oral bioavailability = 25%; Elimination half-life = 2.9 h; Protein binding = 70%