In vitro: ARRY-470(LOXO-101) is a selective kinase inhibitor with nanomolar activity against TRKA, TRKB and TRKC but no other notable kinase inhibition below 1,000 nM. ARRY-470 does not inhibit proliferation of Ba/F3 cells expressing other oncogene targets (epidermal growth factor receptor (EGFR), ALK or ROS1) or of lung and colorectal cell lines that do not harbor an NTRK1 fusion. It induces cell-cycle arrest in G1 and apoptosis of KM12 cells.
In vivo: Early/sustained but not late/acute administration of ARRY-470(LOXO-101) markedly attenuates bone cancer pain and significantly blocks the ectopic sprouting of sensory nerve fibers and the formation of neuroma-like structures in the tumor bearing bone, but does not have a significant effect on tumor growth or bone remodeling. It has very limited ability crossing of the blood brain barrier
|Cell lines||Ba/F3 cells|
|Preparation method||Ba/F3 cells expressing MPRIP-NTRK1 (RIP-TRKA) or EV were lysed after 5 h of treatment with the indicated doses of drugs (ARRY-470; G, gefitinib 1,000 nM) or DMSO control. The cell lysate are used for western bolt analysis.|
|Concentrations||10, 100, 1000 nM|
|Incubation time||5 h|
|Animal models||Adult male C3H/HeJ 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||100 mg/mL in DMSO|
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-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.
LOXO-101 is a potent, ATP competitive TRK inhibitor with IC50s in low nanomolar range for inhibition of all TRK family members in binding and cellular assays, with 100x selectivity over other kinases, with 2 to 20 nM cellular potency against the TRKA, TRKB, and TRKC kinases.
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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