In vitro: Larotrectinib (LOXO-101) was evaluated for off-target kinase enzyme inhibition against a panel of 226 non-TRK kinases at a compound concentration of 1,000 nM and ATP concentrations near the Km for each enzyme. LOXO-101 demonstrated greater than 50% inhibition for only one non-TRK kinase (TNK2 IC50 = 576 nM).
In vivo: A single dose (30 mg/kg) of LOXO-101 reduced tyrosine phosphorylation of TRKA and downstream signal transduction (pERK) in the tumor >80%. LOXO-101 was well tolerated up to 200 mg/kg/day for 14 d in this model.
|Source||Cancer Discov (2015). Figure 1. LOXO-101|
|Cell Lines||CUTO-3.29 cells|
|Incubation Time||2 h|
|Results||pAKT was not inhibited in the CUTO-3.29 cells by LOXO-101 suggesting that TRK signaling is not AKT-dependent in this tumor.|
|Cell lines||KM12 cells|
|Preparation method||Dose-dependent inhibition with LOXO-101 is demonstrated in three cancer cell line models of oncogenic TRK.|
|Animal models||Athymic nude mice|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for Compound A of 10 mg/kg.
|Solubility||4 mg/mL in DMSO|
|Related Trk Products|
|MRTX849 ethoxypropanoic acid
LC-2 is a potent, first-in-class PROTAC capable of degrading endogenous KRAS G12C (DC50, between 0.25 and 0.76 μM).
Tavilermide is a selective, partial agonist of TrkA, or a nerve growth factor (NGF) mimetic.
|Cyclotraxin B acetate
Cyclotraxin B acetate, a cyclic peptide, is a highly potent and selective TrkB inhibitor without altering the binding of BDNF.
AZ-23 is an ATP-competitive and orally bioavailable Trk kinase A/B/C inhibitor with IC50s of 2 nM (TrkA), 8 nM (TrkB), 24 nM (FGFR1), 52 nM (Flt3), 55 nM (Ret), 84 nM (MuSk), 99 nM (Lck), respectively.
Selitrectinib (LOXO-195) is a potent and selective, next-generation TRK inhibitor, with IC50 values of 0.6±0.1 nM, <2.5 nM for TRKA and TRKC, respectively.
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