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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.
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Source | Cancer Discov (2015). Figure 1. LOXO-101 |
| Method | MTS assay | |
| Cell Lines | CUTO-3.29 cells | |
| Concentrations | 100 nM | |
| 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 Experiment | |
|---|---|
| Cell lines | KM12 cells |
| Preparation method | Dose-dependent inhibition with LOXO-101 is demonstrated in three cancer cell line models of oncogenic TRK. |
| Concentrations | 100 nM |
| Incubation time | 24h |
| Animal Experiment | |
|---|---|
| Animal models | Athymic nude mice |
| Formulation | |
| Dosages | 60 mg/kg |
| Administration | oral gavage |
| Species | Mouse | Rat | Rabbit | Guinea pig | Hamster | Dog |
| Weight (kg) | 0.02 | 0.15 | 1.8 | 0.4 | 0.08 | 10 |
| Body Surface Area (m2) | 0.007 | 0.025 | 0.15 | 0.05 | 0.02 | 0.5 |
| Km factor | 3 | 6 | 12 | 8 | 5 | 20 |
| 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.
| Molecular Weight | 428.44 |
| Formula | C21H22F2N6O2 |
| CAS Number | 1223403-58-4 |
| Purity | 99.56% |
| Solubility | 4 mg/mL in DMSO |
| Storage | at -20°C |
| Related Trk Products |
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| 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
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
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)
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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