Selitrectinib (LOXO-195) (Synonyms: Selitrectinib) |
| Catalog No.GC32808 |
Selitrectinib (LOXO-195) (LOXO-195) is a next-generation TRK kinase inhibitor, with IC50s of 0.6 nM and <2.5 nM for TRKA and TRKC, respectively.
Products are for research use only. Not for human use. We do not sell to patients.
Cas No.: 2097002-61-2
Sample solution is provided at 25 µL, 10mM.
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Selitrectinib (LOXO-195) is a next-generation TRK kinase inhibitor (TKI), with IC50s of 0.6 nM, <2.5 nM for TRKA and TRKC respectively.
Selitrectinib (LOXO-195) demonstrates strong binding to the wild-type TRKA, TRKB and TRKC kinase domains. Selitrectinib (LOXO-195) has potent (IC50<1 nM) inhibitory activity in kinase enzyme assays. Importantly, Selitrectinib (LOXO-195) achieves low nanomolar inhibitory activity against TRKA G595R, TRKC G623R, and TRKA G667C, with IC50s ranging from 2.0-9.8 nM. 228 individual kinases in vitro are profiled at a Selitrectinib (LOXO-195) concentration of 1 μM, which is ~1667-fold higher than its IC50 for TRKA (0.6 nM). Selitrectinib (LOXO-195) is more than 1000-fold selective for 98% of non-TRK kinases tested. Selitrectinib (LOXO-195) demonstrates potent inhibition of cell proliferation in TRK fusion-containing KM12, CUTO-3, and MO-91 cell lines (IC50≤5 nM)[1].
Stably transfected NIH-3T3 δTRKA and δTRKA-G595R cells are implanted subcutaneously into the flanks of nude mice. Both larotrectinib and Selitrectinib (LOXO-195) are effective at reducing phosphorylated TRKA in tumors driven by δTRKA. In contrast, only Selitrectinib (LOXO-195) strongly suppresses phospho-TRKA in δTRKA-G595R cells in a dose-dependent manner. Selitrectinib (LOXO-195) also causes inhibition of tumor growth relative to vehicle at all doses in four TRKA-dependent tumor models (δTRKA, δTRKA-G595R, δTRKAG667C, and TPM3-NTRK1 fusion-positive KM12 colorectal cancer cells. Larotrectinib inhibits KM12 and NIH 3T3-δTRKA tumors to a similar degree. Group mean body weight loss does not exceed 5% for any agent. Selitrectinib (LOXO-195) displays high selectivity for the TRK proteins[1]
[1]. Drilon A, et al. A Next-Generation TRK Kinase Inhibitor Overcomes Acquired Resistance to Prior TRK Kinase Inhibition in Patients with TRK Fusion-Positive Solid Tumors. Cancer Discov. 2017 Sep;7(9):963-972.
Cell experiment: | For assessment of cellular inhibition potency, cells are harvested per a standard protocol, counted and added to flat-bottom, collagen I-coated 96-well assay plates at 3×104 cells/well (wild-type cell line) or 5×104 cells/well (mutant cell lines) in 100 μL/well of DMEM growth medium containing 10% FBS. Plates are then incubated at room temperature for 30 minutes prior to an overnight incubation at 37°C with 5% CO2. Next, cells are treated for 1 hour at 37°C, 5% CO2 with TRK inhibitor compounds (e.g., Selitrectinib (LOXO-195)). Control wells contain either 0.25% DMSO alone or 1 μM larotrectinib or LOXO-195. Following compound incubation, growth medium is discarded and cells are lysed by addition of 60 μL/well of ice-cold lysis buffer containing protease and phosphatase inhibitors[1]. |
Animal experiment: | Mice[1]The ΔTRKA, ΔTRKA-G595R, and ΔTRKA -G667C NIH-3T3 tumor cell lines (~2-3x106 cells) and KM12 cells (5x106 cells) are injected subcutaneously into the right flank of female nu/nu NCr mice. Tumors are allowed to grow to ~100-200 mm3 or ~500 mm3, and animals are randomized by tumor size into dosing groups of 5 (KM12), 7 (NIH 3T3 ΔTRKA variants) or 3-4 (for PK-PD) animals. Animals are dosed by oral gavage with vehicle, Selitrectinib (LOXO-195) in 1% carboxymethylcellulose/0.5% Tween-80 or larotrectinib in 100% Labrafac lipophile. All animals are obtained at 6-8 weeks of age, housed in groups of 5 and allowed a one-week acclimation period before cancer cell injection. Animals are dosed with vehicle twice daily, Selitrectinib (LOXO-195) at 30 mg/kg, 100 mg/kg and 300 mg/kg twice daily and larotrectinib at 60 mg/kg daily for 9-12 days. Body weight and tumor size are monitored after cell implantation and at regular intervals during dosing[1]. |
References: [1]. Drilon A, et al. A Next-Generation TRK Kinase Inhibitor Overcomes Acquired Resistance to Prior TRK Kinase Inhibition in Patients with TRK Fusion-Positive Solid Tumors. Cancer Discov. 2017 Sep;7(9):963-972. | |
| Cas No. | 2097002-61-2 | SDF | |
| Synonyms | Selitrectinib | ||
| Canonical SMILES | FC1=CN=C(CC[C@H](N2)C)C([C@](CCC3)([H])N3C(C=CN4N=C5)=NC4=C5C2=O)=C1 | ||
| Formula | C20H21FN6O | M.Wt | 380.42 |
| Solubility | DMSO : 62.5 mg/mL (164.29 mM) | Storage | Store at -20°C |
| General tips | Please select the appropriate solvent to prepare the stock solution according to the
solubility of the product in different solvents; once the solution is prepared, please store it in
separate packages to avoid product failure caused by repeated freezing and thawing.Storage method
and period of the stock solution: When stored at -80°C, please use it within 6 months; when stored
at -20°C, please use it within 1 month. To increase solubility, heat the tube to 37°C and then oscillate in an ultrasonic bath for some time. |
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| Shipping Condition | Evaluation sample solution: shipped with blue ice. All other sizes available: with RT, or with Blue Ice upon request. | ||
| Prepare stock solution | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.6287 mL | 13.1434 mL | 26.2867 mL |
| 5 mM | 0.5257 mL | 2.6287 mL | 5.2573 mL |
| 10 mM | 0.2629 mL | 1.3143 mL | 2.6287 mL |
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- Purity: >99.00%
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