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Purity: =99.58%
Larotrectinib sulfate (LOXO-101; ARRY-470; Vitrakvi), the suldate salt of Larotrectinib, is a potent, oral, selective, ATP-competitive TRK inhibitor with IC50s in the low nanomolar range (2 to 20 nM) for inhibition of all TRK family members in binding and cellular assays. It is 2 to 20 nM cellular potent against the TRKA, TRKB, and TRKC kinases, and it has 100x selectivity over other kinases alike. With ATP concentrations around the Km and LOXO-101 at a concentration of 1,000 nM, the drug's ability to inhibit off-target kinase enzymes was assessed against a panel of non-TRK kinases. Preclinical models of LOXO-101 utilizing human-derived cancer cell lines bearing TRK fusions show inhibition of tumor growth in vivo, in vitro cell proliferation, and the fusion oncoprotein. After being designated as a breakthrough therapy in 2016 for the treatment of metastatic solid tumors with NTRK fusion and as an orphan drug in 2015 for soft tissue sarcoma, larotrectinib was finally approved by the FDA on November 26, 2018. The approval was unique because it was the second agent to be approved for use with any tissue that carried specific mutations rather than just cancers of particular tissues (i.e., tissue agnostic" approval).
| Targets |
TrkC; TrkB; TrkA
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|---|---|
| ln Vitro |
Larotrectinib (LOXO-101) is an ATP-competitive oral inhibitor that targets the three isoforms of the tropomyosin-related kinase (TRK) family of receptor kinases (TRKA, B, and C). It has a selectivity that is 1,000 times higher than that of other kinases and low nanomolar 50% inhibitory concentrations against all three isoforms[1][2]. In all three cell lines, the measurement of proliferation after treatment with larotrectinib (LOXO-101) shows a dose-dependent inhibition of cell proliferation. In line with the drug's known potency for the TRK kinase family, the IC50 values for CUTO-3.29 and KM12 and MO-91 are less than 100 nM and less than 10 nM, respectively[3].
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| ln Vivo |
Larotrectinib (LOXO-101) exhibits 60-65% plasma protein binding and 33-100% oral bioavailability in rat and monkey experiments. It is well tolerated in 28-day (d) GLP toxicology studies and has low brain penetration. Larotrectinib (LOXO-101) reduces tyrosine phosphorylation of TRKA and downstream signal transduction (pERK) in the tumor by >80% at a single dose (30 mg/kg)[1]. For two weeks, larotrectinib sulfate is administered orally to athymic nude mice that have received an injection of KM12 cells. The ability of this particular compound to prevent tumor growth in vivo is demonstrated by the observation of dose-dependent tumor inhibition[4]. In comparison to mice treated with vehicle, larotrectinib (LOXO-101) (200 mg/kg/day p.o. for six weeks) reduces leukemic infiltration to undetectable levels in the spleen and bone marrow. Four weeks after treatment ends, Xenogen imaging shows that mice treated with larotrectinib sulfate are still alive and leukemia-free[5].
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| Enzyme Assay |
LOXO-101 is a small molecule with a cellular potency of 2 to 20 nM against the TRKA, TRKB, and TRKC kinases that was created to block the ATP binding site of the TRK family of receptors. Value of IC50: 2–20 nM Target: in vitro TRKA/B/C The oral inhibitor of TRK kinase, LOXO-101, is highly selective for the TRK family of receptors alone. Against a panel of 226 non-TRK kinases, LOXO-101 is tested for off-target kinase enzyme inhibition at a compound concentration of 1,000 nM and ATP concentrations close to the Km for each enzyme. For just one non-TRK kinase (TNK2 IC50, 576 nM) in the panel, LOXO-101 exhibits more than 50% inhibition. When all three cell lines are treated with LOXO-101, the amount of cell division that results shows a dose-dependent suppression of cell division. Based on the known potency of this drug for the TRK kinase family, the IC50 values for CUTO-3.29 and KM12 and MO-91 are less than 100 nM and less than 10 nM, respectively.
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| Cell Assay |
Ba/F3 cells expressing EV or MPRIP-NTRK1 (RIP-TRKA) were lysed following a 5-hour treatment with the indicated drug doses (ARRY-470; G, gefitinib 1,000 nM) or DMSO control. For western bolt analysis, the cell lysate is used.
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| Animal Protocol |
Mice: Throughout the investigation, arthymic nude mice are employed. The mice are given a subcutaneous injection of 5x105 KM12 cells into the dorsal flank region. Tumor volume is measured directly with calipers and is computed using the following formula: length × (width5)/2. Mice are randomly chosen to receive either diluent, 60 mg/kg/dose, or 200 mg/kg/dose of Larotrectinib (LOXO-101) after the tumor has established and reached a size of 150–200 mm5. For 14 days, larotrectinib (LOXO-101) is given orally via gavage once a day. Three, six, and twenty-four hours after the final dosage, tissue and blood are extracted[4].
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| References |
| Molecular Formula |
C21H22F2N6O2.H2O4S
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|---|---|
| Molecular Weight |
526.51
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| Exact Mass |
526.14461
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| Elemental Analysis |
C, 47.91; H, 4.59; F, 7.22; N, 15.96; O, 18.23; S, 6.09
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| CAS # |
1223405-08-0
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| Related CAS # |
Larotrectinib;1223403-58-4;(R)-Larotrectinib;1223404-68-9
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| Appearance |
Solid powder
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| SMILES |
C1C[C@@H](N(C1)C2=NC3=C(C=NN3C=C2)NC(=O)N4CC[C@@H](C4)O)C5=C(C=CC(=C5)F)F.OS(=O)(=O)O
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| InChi Key |
PXHANKVTFWSDSG-QLOBERJESA-N
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| InChi Code |
InChI=1S/C21H22F2N6O2.H2O4S/c22-13-3-4-16(23)15(10-13)18-2-1-7-28(18)19-6-9-29-20(26-19)17(11-24-29)25-21(31)27-8-5-14(30)12-27;1-5(2,3)4/h3-4,6,9-11,14,18,30H,1-2,5,7-8,12H2,(H,25,31);(H2,1,2,3,4)/t14-,18+;/m0./s1
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| Chemical Name |
(3S)-N-[5-[(2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidin-3-yl]-3-hydroxypyrrolidine-1-carboxamide;sulfuric acid
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| Synonyms |
ARRY 470 sulfate; ARRY-470 sulfate; ARRY470 sulfate; LOXO-101 sulfate; Larotrectinib sulfate; LOXO101 sulfate; LOXO 101 sulfate; LOXO-101; LOXO101; ARRY-470; ARRY470; ARRY 470; trade name: Vitrakvi
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 3.25 mg/mL (6.17 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 32.5 mg/mL clear DMSO stock solution to 400 μL of PEG300 and mix evenly; then add 50 μL of Tween-80 to the above solution and mix evenly; then add 450 μL of normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 3.25 mg/mL (6.17 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 32.5 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 3.25 mg/mL (6.17 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: ≥ 2.5 mg/mL (4.75 mM) (saturation unknown) in 5% DMSO + 40% PEG300 + 5% Tween80 + 50% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 5: ≥ 2.5 mg/mL (4.75 mM) (saturation unknown) in 5% DMSO + 95% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. Solubility in Formulation 6: 12.5 mg/mL (23.74 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.8993 mL | 9.4965 mL | 18.9930 mL | |
| 5 mM | 0.3799 mL | 1.8993 mL | 3.7986 mL | |
| 10 mM | 0.1899 mL | 0.9496 mL | 1.8993 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT04879121 | Recruiting | Drug: Larotrectinib Sulfate | Locally Advanced Malignant Solid Neoplasm Metastatic Malignant Solid Neoplasm |
M.D. Anderson Cancer Center | April 30, 2021 | Phase 2 |
| NCT03834961 | Active Recruiting |
Drug: Larotrectinib Sulfate | Solid Neoplasm Infantile Fibrosarcoma |
Children's Oncology Group | September 18, 2019 | Phase 2 |
| NCT03213704 | Recruiting | Drug: Larotrectinib Sulfate Procedure: Bone Scan |
Recurrent Glioma Refractory Glioma |
National Cancer Institute (NCI) |
August 23, 2017 | Phase 2 |
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