Mechanism of Action of Larotrectinib
Larotrectinib is an ATP-competitive, small-molecule inhibitor that selectively and potently targets the tropomyosin receptor kinases TRKA, TRKB, and TRKC, with IC50 values in the range of 5-11 nM. 1
Molecular Target and Selectivity
Larotrectinib inhibits all three TRK proteins (TRKA, B, and C) encoded by the NTRK1, NTRK2, and NTRK3 genes with half-maximal inhibitory concentrations between 5-11 nM 1
The drug demonstrates exceptional selectivity, with binding affinities over 100-fold greater for TRK proteins compared to a panel of other kinases 2
In comprehensive enzyme assays, larotrectinib inhibited no other tested kinases at concentrations up to 500-1,000 nM, with only one other kinase (TNK2) inhibited at approximately 100-fold higher concentration 2, 1
Mechanism of Oncogenic Inhibition
Larotrectinib works by blocking constitutively-activated chimeric TRK fusion proteins that result from chromosomal rearrangements involving in-frame fusions of NTRK genes with various partner genes 1
These NTRK gene fusions produce fusion proteins with constitutive tyrosine kinase activity that act as primary oncogenic drivers, promoting cell proliferation and survival in tumor cells 2
The drug demonstrated anti-tumor activity specifically in cells with constitutive TRK activation resulting from gene fusions, deletion of protein regulatory domains, or TRK protein overexpression 1
Clinical Implications of the Mechanism
Larotrectinib's ATP-competitive mechanism allows it to bind to the ATP-binding pocket of the TRK kinase domain, preventing downstream oncogenic signaling 2
The drug had minimal activity against cells with point mutations in the TRKA kinase domain, including the clinically identified acquired resistance mutation G595R 1
Known resistance mutations in the TRKC kinase domain include G623R, G696A, and F617L, which can develop after initial response to treatment 1
The high selectivity translates to a favorable safety profile, as the drug does not significantly inhibit off-target kinases that could cause additional toxicities 2