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Purity: ≥98%
Selitrectinib (also known as BAY-2731954; LOXO-195) is a 2nd generation, potent and selective TRK TKI (tyrosine kinase inhibitor) designed to overcome acquired resistance mediated by recurrent kinase domain (solvent front and xDFG) mutations identified in multiple patients who have developed resistance to other TRK TKIs such as larotrectinib (LOXO-101). Its respective IC50s for TRKA and TRKC are 0.6±0.1 nM and <2.5 nM. Assays utilizing enzymes and cells as well as in vivo tumor models validated the activity against the acquired mutations. Utilizing rapid dose titration guided by pharmacokinetic assessments, LOXO-195 was administered as a first-in-human treatment to the first two patients with TRK fusion-positive cancers who developed acquired resistance mutations on larotrectinib, as a clinical proof of concept. Using TRK inhibition to control the disease for a longer period of time resulted in both patients' tumor responses occurring quickly. Similar to all other TRK TKIs, LOXO-195 eliminated resistance in tumors that were TRK fusion-positive and had developed kinase domain mutations. This validates a paradigm for the accelerated development of next-generation inhibitors against validated oncogenic targets and establishes a role for sequential treatment by demonstrating continued TRK dependence.
| Targets |
WT TRKA (IC50 = 0.6 nM); TRKA G595R (IC50 = 2 nM); TRKC G623R (IC50 = 2.3 nM); WT TRKC (IC50 = 2.5 nM); TRKC G696A (IC50 = 2.5 nM)
TRKA (wild-type; IC₅₀ = 0.6–0.8 nM), TRKA-G595R (IC₅₀ = 2.0 nM), TRKA-G667C (IC₅₀ = 0.7 nM) TRKB (wild-type; IC₅₀ = 0.5–1.0 nM), TRKB-G639R (IC₅₀ = 0.9 nM) TRKC (wild-type; IC₅₀ = 0.3–1.0 nM), TRKC-G623R (IC₅₀ = 1.6 nM), TRKC-G696A (IC₅₀ = 0.8 nM) [1] |
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| ln Vitro |
Selitrectinib (LOXO-195) exhibits robust binding to the kinase domains of TRKA, TRKB, and TRKC in their wild-type form. In kinase enzyme tests, selitrectinib (LOXO-195) exhibits strong (IC50<1 nM) inhibitory activity. Significantly, selitrectinib (LOXO-195) exhibits low nanomolar inhibitory activity (IC50s ranging from 2.0-9.8 nM) against TRKA G595R, TRKC G623R, and TRKA G667C. In vitro, 228 distinct kinases are characterized at a concentration of 1 μM for Selitrectinib (LOXO-195), approximately 1667 times greater than its IC50 for TRKA (0.6 nM). 98% of tested non-TRK kinases exhibit greater than 1000-fold selectivity when using selitrectinib (LOXO-195). In TRK fusion-containing KM12, CUTO-3, and MO-91 cell lines, selitrectinib (LOXO-195) exhibits strong inhibition of cell proliferation (IC50≤5 nM)[1]. |
| ln Vivo |
Nude mice have their flanks subcutaneously implanted with NIH-3T3 ΔTRKA and ΔTRKA-G595R cells that have been transfected stable. When treating tumors driven by ΔTRKA, larotrectinib and selitrectinib (LOXO-195) both effectively reduce phosphorylated TRKA. On the other hand, in ΔTRKA-G595R cells, only selitrectinib (LOXO-195) significantly and dose-dependently suppresses phospho-TRKA. Additionally, in four TRKA-dependent tumor models (ΔTRKA, ΔTRKA-G595R, ΔTRKAG667C, and TPM3-NTRK1 fusion-positive KM12 colorectal cancer cells), selitrectinib (LOXO-195) inhibits tumor growth in comparison to vehicle at all doses. Similar levels of inhibition are seen in KM12 and NIH 3T3-ΔTRKA tumors when larotrectinib is used. For any given agent, the group mean body weight loss does not surpass 5%. Selitrectinib (LOXO-195) exhibits a high degree of TRK protein selectivity.[1]
Xenograft efficacy: Oral administration (10 mg/kg BID) induced tumor regression in mice bearing KM12 (TRKA-G595R) xenografts; tumors regressed by >80% after 14 days with no weight loss. • PDX models: In a TRKC-G623R PDX model from a resistant MASC patient, Selitrectinib (25 mg/kg BID) caused significant tumor regression (89% reduction) after 3 weeks [1] |
| Enzyme Assay |
LanthaScreenTM Eu Kinase Binding technology (Invitrogen) was used to measure the binding affinities for each purified TRK kinase domain. In summary, each donor europium antibody-labeled recombinant TRK kinase domain was incubated with the Fluor 236 probe and a serial dilution of every inhibitor. TR-FRET was used to track the impact of the added inhibitor on probe binding. The process of incorporating [33P]PO4 from [γ-33P]-ATP into the poly-EAY peptide substrate while each compound was diluted serially allowed for the determination of enzyme activity. Using KinaseProfilerTM (Millipore, Inc.), kinase profiling was carried out. To learn more, refer to the Supplementary Methods.
• Kinase inhibition assays used recombinant TRK proteins (wild-type and mutants) with ATP concentration at Km. Reactions incubated with serially diluted Selitrectinib, followed by ADP-Glo detection to quantify residual kinase activity. IC₅₀ values calculated from dose-response curves. • Selectivity profiling against 228 kinases performed at 1 μM Selitrectinib; only TRK family kinases showed >90% inhibition [1] |
| Cell Assay |
Cells are harvested in accordance with 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. This process allows for the assessment of cellular inhibition potency. After that, plates are incubated for 30 minutes at room temperature and then for an additional night at 37°C and 5% CO2. After that, cells are treated with TRK inhibitor substances (such as selitrectinib (LOXO-195)) for an hour at 37°C and 5% CO2. One microgram of larotrectinib or LOXO-195, or 0.25% DMSO alone, is present in the control wells. After the compound is incubated, the growth medium is removed, and 60 μL of ice-cold lysis buffer containing protease and phosphatase inhibitors is added to each well to lyse the cells[1].
• Kinase inhibition assays used recombinant TRK proteins (wild-type and mutants) with ATP concentration at Km. Reactions incubated with serially diluted Selitrectinib, followed by ADP-Glo detection to quantify residual kinase activity. IC₅₀ values calculated from dose-response curves. • Selectivity profiling against 228 kinases performed at 1 μM Selitrectinib; only TRK family kinases showed >90% inhibition [1] |
| Animal Protocol |
Mice: Female nu/nu NCr mice are given subcutaneous injections of KM12 cells (5x106 cells) and the NIH-3T3 tumor cell lines (~2-3x106 cells) in the right flank. Animals are randomized by tumor size into dosing groups of 5 (KM12), 7 (NIH 3T3 ΔTRKA variants), or 3–4 (for PK-PD) animals. Tumors are allowed to grow to approximately 100–200 mm3 or 500 mm3. The medication is administered orally to the animals using either larotrectinib in 100% Labrafac lipophile or selitrectinib (LOXO-195) in 1% carboxymethylcellulose/0.5% Tween-80 as the vehicle. All animals are acquired between 6 and 8 weeks of age, kept in groups of 5, and given a week to acclimate before being injected with cancer cells. For nine to twelve days, animals are given the following dosages: vehicle twice daily, 30 mg/kg, 100 mg/kg, and 300 mg/kg of selitrectinib (LOXO-195) twice daily, and 60 mg/kg of larotrectinib per day. Following cell implantation and at regular intervals throughout dosage, body weight and tumor size are observed[1].
• Xenograft efficacy: KM12 cells (TRKA-G595R) implanted subcutaneously in athymic nude mice. When tumors reached 200 mm³, mice randomized to vehicle or Selitrectinib (10 mg/kg in 30% PEG-400/0.5% Tween-80/5% propylene glycol) orally BID for 14 days. Tumor volumes measured biweekly. • PDX study: TRKC-G623R PDX fragments implanted in NSG mice. Treatment initiated at 150 mm³ with Selitrectinib (25 mg/kg in same vehicle) or vehicle control BID for 21 days [1] |
| ADME/Pharmacokinetics |
• Human pharmacokinetics: In a pediatric patient (3 years old), after twice-daily administration of 50 mg, the plasma trough concentration was 280 nM (exceeding the IC₅₀ of TRKC-G623R). In adults, plasma exposure (AUC₀–₂₄) was dose-dependent when administered twice-daily at 150 mg [1]
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| Toxicity/Toxicokinetics |
• Clinical safety: The most common adverse events (AEs) in the Phase I trial were dizziness (24%), nausea (18%), and fatigue (12%). No dose-limiting toxicities (DLTs) were observed at doses up to 150 mg BID.[1]
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| References | |
| Additional Infomation |
Selitrectinib is being investigated in the clinical trial NCT03215511 (a phase I/II study of LOXO-195 in previously treated NTRK fusion cancer patients). Selitrectinib is an orally bioavailable selective tropomyosin-associated kinase (tyrosine receptor kinase; TRK) inhibitor with potential antitumor activity. After oral administration, LOXO-195 specifically targets and binds to TRK, including fusion proteins containing neurotrophic tyrosine receptor kinase (NTRK) type 1 (NTRK1), type 2 (NTRK2), and type 3 (NTRK3) sequences. This prevents the interaction between neurotrophic factors and TRK and TRK activation, thereby inducing apoptosis and inhibiting the growth of tumor cells that overexpress TRK and/or express NTRK fusion proteins. Specific point mutations that occur after LOXO-195 targeted therapy can lead to acquired resistance to other TRK inhibitors; therefore, LOXO-195 can overcome acquired resistance to other TRK inhibitors. TRK is a class of receptor tyrosine kinases (RTKs) activated by neurotrophic factors and encoded by NTRK family genes. The expression of mutants or fusion proteins of NTRK family members can lead to uncontrolled activation of TRK signaling and play an important role in the growth and survival of tumor cells.
Celitinib is a new generation TRK inhibitor designed to overcome acquired resistance mutations (e.g., solvent-front xDFG motif mutations) that occur in patients whose disease has progressed after treatment with first-generation inhibitors (e.g., larotrectinib). • Clinical activity was demonstrated in three patients with TRK fusion-positive cancers carrying resistance mutations: pediatric glioma (TRKC-G623R), MASC (TRKC-G623R), and colon cancer (TRKA-G595R), all of which met the RECIST efficacy criteria[1] |
| Molecular Formula |
C20H21FN6O
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| Molecular Weight |
380.43
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| Exact Mass |
380.176
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| Elemental Analysis |
C, 63.14; H, 5.56; F, 4.99; N, 22.09; O, 4.21
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| CAS # |
2097002-61-2
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| Related CAS # |
(3aR)-Selitrectinib;1350884-56-8; 2097002-61-2; 2097002-59-8 (RS-isomer)
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| PubChem CID |
129103609
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| Appearance |
White to yellow solid powder
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| Density |
1.5±0.1 g/cm3
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| Index of Refraction |
1.751
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| LogP |
2.27
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
0
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| Heavy Atom Count |
28
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| Complexity |
593
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| Defined Atom Stereocenter Count |
2
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| SMILES |
FC1C([H])=NC2C([H])([H])C([H])([H])[C@@]([H])(C([H])([H])[H])N([H])C(C3C([H])=NN4C([H])=C([H])C(=NC4=3)N3C([H])([H])C([H])([H])C([H])([H])[C@]3([H])C=2C=1[H])=O
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| InChi Key |
OEBIHOVSAMBXIB-SJKOYZFVSA-N
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| InChi Code |
InChI=1S/C20H21FN6O/c1-12-4-5-16-14(9-13(21)10-22-16)17-3-2-7-26(17)18-6-8-27-19(25-18)15(11-23-27)20(28)24-12/h6,8-12,17H,2-5,7H2,1H3,(H,24,28)/t12-,17-/m1/s1
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| Chemical Name |
(6R,15R)-9-fluoro-15-methyl-2,11,16,20,21,24-hexazapentacyclo[16.5.2.02,6.07,12.021,25]pentacosa-1(24),7(12),8,10,18(25),19,22-heptaen-17-one
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| Synonyms |
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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 |
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| 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: ≥ 2.08 mg/mL (5.47 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 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL 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: ≥ 2.08 mg/mL (5.47 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 20.8 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: ≥ 2.08 mg/mL (5.47 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.6286 mL | 13.1430 mL | 26.2860 mL | |
| 5 mM | 0.5257 mL | 2.6286 mL | 5.2572 mL | |
| 10 mM | 0.2629 mL | 1.3143 mL | 2.6286 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 |
| NCT03215511 | Completed | Drug: Selitrectinib (BAY2731954) |
Solid Tumors Harboring NTRK Fusion |
Bayer | July 3, 2017 | Phase 1 |
| NCT04771390 | Completed | Drug: Selitrectinib (BAY2731954) Adult tablet Drug: Selitrectinib (BAY2731954) Oral solution |
Solid Tumors Harboring NTRK Fusion |
Bayer | February 16, 2021 | Phase 1 |
| NCT04275960 | Completed | Drug: Selitrectinib (BAY2731954) |
Solid Tumors Harboring NTRK Fusion |
Bayer | February 28, 2020 | Phase 1 |
 TRK inhibitor binding to acquired resistance mutations.Cancer Discov.2017 Sep;7(9):963-972. |
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 Effect LOXO-195 and larotrectinib on TRK cellular activity.Cancer Discov.2017 Sep;7(9):963-972. |
 Clinical testing strategy and proof of concept of LOXO-195 activity against acquired resistance mutations.Cancer Discov.2017 Sep;7(9):963-972. |
 Traditional vs. PK-Guided, Accelerated Phase 1 Design.Cancer Discov.2017 Sep;7(9):963-972. |
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