Larotrectinib

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Mechanism of Action

Larotrectinib is a selective and potent inhibitor of TRKA, TRKB and TRKC, with IC₅₀ values in the low nanomolar range for inhibition of all three TRK protein family members [1, 2]. In addition, larotrectinib is 100-fold more selective for the TRK protein than for other kinase and non-kinase targets.

Proliferation assays in human-derived cancer cell lines (lung adenocarcinoma, colorectal cancer, and acute myeloid leukaemia) demonstrated that larotrectinib inhibited cell proliferation in all three cell lines [3]. In addition, larotrectinib inhibited tumour growth in vivo in mice with human colorectal cancer xenografts. 

References

1. Burris HA, Shaw AT, Bauer TM et al. Abstract 4529: Pharmacokinetics (PK) of LOXO-101 during the first-in-human Phase I study in patients with advanced solid tumors: Interim update. Cancer Research 2015; 75: 4529.
2. Cocco E, Scaltriti M, Drilon A. NTRK fusion-positive cancers and TRK inhibitor therapy. Nat Rev Clin Oncol 2018; 15: 731-747.
3. Doebele RC, Davis LE, Vaishnavi A 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; 5: 1049-1057.