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| Targets |
ROS1/NTRK
Taletrectinib targets ROS1 and TRK kinases. By inhibiting these kinases, it blocks the downstream signaling pathways that promote tumor cell proliferation and survival. It is being studied for the treatment of cancers that involve ROS1 gene fusions, such as non-small cell lung cancer. Its activity against ROS1 and TRK makes it a valuable tool for studying these oncogenic drivers. |
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| ln Vitro |
The half-life of taletrectinib (1-1000 nM; 72 hours) against Ba/F3-TPM3-NTRK1, Ba/F3-ETV6-NTRK1, -NTRK2, -NTRK3, or KM12 cells is approximately 3–20 nM [1]. In U-118-MG cells, taletrectinib (0.001-1000 nM; 2 hours) dose-dependently inhibits ROS1 autophosphorylation [1]. ROS1 autophosphorylation in JFCR-165, JFCR-168, and MGH193-1B cells is efficiently inhibited by taletrectinib [1]. Phosphorylated NTRK1 is somewhat inhibited by taletrectinib at 10 nM and totally inhibited at 100 nM. Recombinant ROS1, NTRK1, and NTRK3 are potently inhibited by taletrectinib at subnanomolar concentrations in an ATP-competitive manner. When 1 mM ATP is present, 0.2 μM taletrectinib almost totally inhibits 160 kinases, including ACK, ALK, DDR1, and LTK, but not the other 152 kinases [1]. CRISPOTINIB-resistant ROS1 secondary mutations, such as the G2032R solvent front mutation, are effectively inhibited by taletrectinib [1].
In vitro, Taletrectinib has been shown to be a potent inhibitor of ROS1 and TRK kinase activity. Its inhibitory activity is typically assessed using kinase assays that measure the phosphorylation of a substrate in the presence of the compound. These in vitro studies confirm its potential as a therapeutic agent for ROS1- and TRK-driven cancers. |
| ln Vivo |
Taletrectinib adipate (DS-6051b) (25 -200 mg/kg; oral; once daily for 18 days) shows anti-tumor activity[1]. Taletrectinib (6.25 -200 mg/kg; oral; once daily for 8 days) inhibits NTRK-rearranged cancer in Balb-c nu/nu mice harboring KM12 cells[1]. Taletrectinib (3-100 mg/kg; oral; once daily for 4 days) shows rapid tumor regression in wild-type (WT) and G2032R mutant Ba/F3 mice without severe weight loss[1].
In vivo, Taletrectinib has demonstrated anti-tumor activity in animal models of ROS1- and TRK-driven cancers. The adipate salt form enhances its solubility and bioavailability, improving its pharmacokinetic profile. These studies provide evidence for its therapeutic potential. |
| Enzyme Assay |
Kinase selectivity profiling[1]
An off-chip mobility shift assay was performed. The effect of DS-6051b at a concentration of 200 nM on 160 kinases was evaluated in the presence of 1 mM ATP and expressed as % inhibition. Inhibitory activities of DS-6051b on ACK, ALK, DDR1, DDR2, KIT, LTK, ROS1, NTRK1, NTRK2, NTRK3, and TXK were determined by the mobility shift assay. ATP concentration in the assay was set at the approximate Km value of each kinase for ATP or 1 mM. The IC50 values were estimated according to the four-parameter logistic model. Cell-free assays for Taletrectinib adipate typically involve measuring its inhibitory activity against ROS1 and TRK kinases using biochemical kinase assays. The compound's IC50 values are determined by measuring the phosphorylation of a substrate in the presence of varying concentrations of the compound. These assays are used to characterize the compound's potency and selectivity. |
| Cell Assay |
Cell Viability Assay[1]
Cell Types: TPM3-NTRK1-induced Ba/F3 cells, KM12 cells Tested Concentrations: 1-1000 nM Incubation Duration: 72 hrs (hours) Experimental Results: Inhibited TPM3-NTRK1-induced Ba/F3 cells and KM12 cells viability. Western Blot Analysis[1] Cell Types: U-118 MG cells (harboring FIG-ROS1 fusion gene) Tested Concentrations: 0.001-1000 nM Incubation Duration: 2 hrs (hours) Experimental Results: Dose dependently inhibited autophosphorylation of ROS1 in U-118-MG cells. In vitro cellular assays are conducted to evaluate the functional activity of Taletrectinib adipate. Cancer cell lines driven by ROS1 or TRK fusions are treated with the compound, and cell proliferation is measured to assess its anti-proliferative activity. ROS1 and TRK phosphorylation are measured to assess the inhibition of kinase signaling. These assays confirm that Taletrectinib effectively blocks ROS1- and TRK-mediated cellular responses. |
| Animal Protocol |
Animal/Disease Models: Balb-c nu/nu (nude) mice (bearing U-118 MG cells)[1]
Doses: 25, 50, 100, and 200 mg/kg Route of Administration: Po; one time/day for 18 days Experimental Results: Effectively inhibited tumor growth at ≥25 mg/kg without significant body weight loss. In vivo animal experiments typically involve xenograft models of ROS1- or TRK-driven cancers. Animals are administered the compound via oral gavage. Tumor growth is monitored over time to assess efficacy. Pharmacokinetic studies are conducted to measure plasma concentrations of the compound. These studies provide evidence for the compound's anti-tumor activity. |
| ADME/Pharmacokinetics |
The pharmacokinetic properties of Taletrectinib adipate are characterized by enhanced solubility and bioavailability due to the adipate salt form. Its molecular weight is 551.61. The compound is designed to have favorable drug-like properties, including good oral bioavailability and metabolic stability. Pharmacokinetic studies in animal models involve measuring plasma concentrations of the compound over time.
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| Toxicity/Toxicokinetics |
The toxicity profile of Taletrectinib adipate is not extensively documented, but it is likely to be similar to other ROS1 and TRK inhibitors. Common adverse effects may include fatigue, diarrhea, and edema. In preclinical studies, the compound has been shown to be well-tolerated at therapeutic doses, with a safety profile that supports its clinical development.
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| References |
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| Additional Infomation |
Taletrectinib adipic acid is the adipic ester form of Taletrectinib, an orally administered receptor tyrosine kinase inhibitor that inhibits C-ros oncogene 1 (ROS1) and neurotrophic tyrosine receptor kinases (NTRKs) types 1, 2, and 3, possessing potential antitumor activity. After oral administration, Taletrectinib binds to and inhibits ROS1 and NTRK family members. This inhibition leads to the disruption of ROS1 and NTRK-mediated signaling, ultimately suppressing the growth of tumor cells overexpressing ROS1 and/or NTRK. ROS1 is overexpressed in some cancer cells and plays a crucial role in cancer cell growth and survival. NTRK mutations or rearrangements play a key role in cancer progression.
See also: Taletrectinib (Note moved to). Taletrectinib (DS-6051b; AB-106; IBI-344) is a ROS1 and TRK inhibitor being developed for the treatment of cancers with ROS1 gene fusions. The adipate salt form enhances its solubility and bioavailability. It is currently being investigated in clinical trials. |
| Molecular Formula |
C29H34FN5O5
|
|---|---|
| Molecular Weight |
551.61
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| Exact Mass |
551.254
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| Elemental Analysis |
C, 63.14; H, 6.21; F, 3.44; N, 12.70; O, 14.50
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| CAS # |
1505515-69-4
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| Related CAS # |
Taletrectinib free base;1505514-27-1
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| PubChem CID |
72694302
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| Appearance |
Typically exists as white to off-white solids at room temperature
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| LogP |
3-[4-[((2R)-2-Aminopropyl)oxy]phenyl]-N-[(1R)-1-(3-fluorophenyl)ethyl]imidazo[1,2-b]pyridazin-6-amine monoadipate
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| Hydrogen Bond Donor Count |
4
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| Hydrogen Bond Acceptor Count |
10
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| Rotatable Bond Count |
12
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| Heavy Atom Count |
40
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| Complexity |
645
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| Defined Atom Stereocenter Count |
2
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| SMILES |
C[C@H](COC1=CC=C(C=C1)C2=CN=C3N2N=C(C=C3)N[C@H](C)C4=CC(=CC=C4)F)N.C(CCC(=O)O)CC(=O)O
|
| InChi Key |
DORJQZDOULKINH-QNBGGDODSA-N
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| InChi Code |
InChI=1S/C23H24FN5O.C6H10O4/c1-15(25)14-30-20-8-6-17(7-9-20)21-13-26-23-11-10-22(28-29(21)23)27-16(2)18-4-3-5-19(24)12-18;7-5(8)3-1-2-4-6(9)10/h3-13,15-16H,14,25H2,1-2H3,(H,27,28);1-4H2,(H,7,8)(H,9,10)/t15-,16-;/m1./s1
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| Chemical Name |
3-[4-[((2R)-2-Aminopropyl)oxy]phenyl]-N-[(1R)-1-(3-fluorophenyl)ethyl]imidazo[1,2-b]pyridazin-6-amine monoadipate
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| Synonyms |
DS-6051B; DS 6051B; Taletrectinib; 1505515-69-4; DS-6051b; Taletrectinib adipate; DS-6051B adipate; 6KLL51GNBG; Taletrectinib adipate [USAN]; 1505515-69-4 (adipate); DS6051B. AB-106; AB106; AB 106; Taletrectinib adipate;
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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 Note: Please store this product in a sealed and protected environment, avoid exposure to moisture. |
| 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) |
DMSO: 50 mg/mL (90.64 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (3.77 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 (3.77 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 (3.77 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 | 1.8129 mL | 9.0644 mL | 18.1288 mL | |
| 5 mM | 0.3626 mL | 1.8129 mL | 3.6258 mL | |
| 10 mM | 0.1813 mL | 0.9064 mL | 1.8129 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.
Link: https://clinicaltrials.gov/ct2/show/NCT02675491
Conditions:Advanced Solid Malignant TumorsProducts are for research use only; We do not sell to patients
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