In vitro: 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.
|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 resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 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 resveratrol of 11.2 mg/kg.
|Solubility||4.6 mg/mL in DMSO|
|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.|
Infantile Fibrosarcoma With NTRK3-ETV6 Fusion Successfully Treated With the Tropomyosin-Related Kinase Inhibitor LOXO-101.
Nagasubramanian R, et al. Pediatr Blood Cancer. 2016 Aug;63(8):1468-70. PMID: 27093299.
An Oncogenic NTRK Fusion in a Patient with Soft-Tissue Sarcoma with Response to the Tropomyosin-Related Kinase Inhibitor LOXO-101.
Doebele RC, et al. Cancer Discov. 2015 Oct;5(10):1049-57. PMID: 26216294.
|Related Trk Products|
LOXO-101 sulfate is an oral potent and selective ATP-competitive inhibitor of tropomyosin receptor kinases (TRK).
ANA-12 is a selective TrkB antagonist with Kd of 10 nM and 12 μM for the high and low affinity sites, respectively.
GW441756 is a potent, selective inhibitor of TrkA with IC50 of 2 nM, with very little activity to c-Raf1 and CDK2.
GNF-5837 is a potent pan-Trk inhibitor which display antiproliferative effects in cellular Ba/F3 assays (IC50 values are 7, 9 and 11 nM for cells containing the fusion proteins Tel-TrkC, Tel-TrkB and Tel-TrkA, respectively.
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