APS03118
APS03118 is an orally active, potent and selective rearranged during transfection (RET) inhibitor. APS03118 broadly inhibits RET fusions and mutations (including G810, V804, L730, and Y806 variants), with IC50 values predominantly below 1 nM (0.095 nM for WT; ranging from 0.00438 to 5.72 nM for mutants), and demonstrates marked superiority against RET G810 mutations. APS03118 inhibits the entire RET signaling pathway (including RET, Shc, and ERK1/2), with >20-fold selectivity over most off-target kinases (except FLT3 and YES). APS03118 induces complete tumor regression in KIF5B-RET and CCDC6-RET V804 M patient derived xenografts (PDXs) and significantly prolongs survival in an intracranial CCDC6-RET metastasis mice model. APS03118 can be used for selective RET inhibitor (SRI)-resistant, RET-driven cancer research.
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- Purity: 98.99%
- CAS No.: 2598870-24-5
- 화학식: C27H28N8O2
- 분자량:496.56
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보관:Powder -20°C, 3 years , 4°C, 2 years ; In solvent -80°C, 6 months , -20°C, 1 month
To place orders, for customer services and technical support, please contact: MedChemExpress USA
Tel: 609-228-6898 E-mail: [email protected] [email protected]
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Biological Activity
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Chemical Information
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용액&용해도
- 순도&문서
- References
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Help & FAQs
Biological Activity
APS03118 (compound 5) shows markedly superior activity against the solvent-front RET G810 mutation compared to Selpercatinib (HY-114370) and Pralsetinib (HY-112301)[1].
APS03118 exhibits superior efficacy against resistant RET mutations in engineered models (solvent-front and gatekeeper) and also demonstrates potent antiproliferative activity comparable to Pralsetinib and Selpercatinib in a native RET fusion-positive LC2/ad lung cancer cells (IC50 = 10.08 nM)[1].
APS03118 (0-3000 nM) inhibits RET autophosphorylation in Ba/F3 KIF5B-RET, Ba/F3 KIF5B-RET V804M, Ba/F3 KIF5B-RET G810R, and Ba/F3 KIF5B-RET M918T cells with IC50 values of 1.91, 1.18, 14.66, and 2.28 nM[1].
APS03118 (0-1000 nM, 1.5 h) potently inhibits the entire RET signaling pathway (including RET, Shc, and ERK1/2) in TT-RET C634W cells at low nanomolar concentrations[1].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Cell Line:TT-RET C634W cells
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Concentration:0, 1, 10, 100, and 1000 nM
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Incubation Time:1.5 h
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Result:Almost abolished the phosphorylation of RET, Shc and ERK1/2 at 10 nM, whereas Selpercatinib and Pralsetinib only partially inhibited it.
Inhibited the phosphorylation of RET, Shc, and ERK1/2 at concentrations below 10 nM.
| Species | Dose | Route | T1/2 | AUC0-last | Cmax | Tmax | F | AUClast | Vd | CL |
|---|---|---|---|---|---|---|---|---|---|---|
| Dog[1] | 10 mg/kg | p.o. | 1.98 h | 1106 ng·h/mL | 322 ng/mL | 1.67 h | 18.0 % | / | / | / |
| Dog[1] | 2 mg/kg | i.v. | 1.34 h | / | / | / | / | 1228 ng·h/mL | 3.16 L/kg | 26.9 mL/min/kg |
| Monkey[1] | 2 mg/kg | i.v. | 2.23 h | / | / | / | / | 1965 ng·h/mL | 3.62 L/kg | 17.3 mL/min/kg |
| Monkey[1] | 2 mg/kg | p.o. | 2.69 h | 797 ng·h/mL | 122 ng/mL | 4.00 h | 38.9 % | / | / | / |
| Rat[1] | 5 mg/kg | i.v. | 2.68 h | / | / | / | / | 21798 ng·h/mL | 0.849 L/kg | 4.26 mL/min/kg |
| Rat[1] | 5 mg/kg | p.o. | 2.72 h | 13843 ng·h/mL | 2522 ng/mL | 4.00 h | 67.3 % | / | / | / |
APS03118 (10 and 30 mg/kg, p.o., BID for 90 days) eliminates intracranial tumors and prolongs survival in an intracranial CCDC6-RET mice metastasis model[1].
APS03118 (10 and 30 mg/kg, p.o., BID for 14 and 15 days) inhibits tumor growth in Ba/F3 KIF5B-RET G810R and Ba/F3 KIF5B-RET V804M CDX mice models[1].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:Female BALB/c nude mice (6-8 weeks) subcutaneously implanted with KIF5B-RET tumors[1]
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Dosage:3, 10 and 30 mg/kg
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Administration:p.o., BID for 28 days
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Result:Inhibited tumor growth in a dose-dependent manner, with TGI of 85, 107, and 109% at 3, 10, and 30 mg/kg, respectively.
Significantly reduced tumor volumes on day 17 compared to the vehicle.
Achieved complete tumor regression at 10 and 30 mg/kg at the study end point, matching the efficacy of Selpercatinib at its 10 mg/kg dose.
Revealed no significant body weight changes.
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Animal Model:Female BALB/c nude mice (6-8 weeks) subcutaneously implanted with CCDC6-RET V804M tumors[1]
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Dosage:3, 10 and 30 mg/kg
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Administration:p.o., BID for 28 days
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Result:Achieved tumor growth inhibition of 88, 99, and 100%, at 3, 10, and 30 mg/kg, respectively.
Reduced tumor volumes in all tested group.
Reduced tumor size at 3 and 10 mg/kg, with efficacy comparable to Selpercatinib at its 10 mg/kg dose.
Revealed no significant body weight changes.
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Animal Model:Female BALB/c nude mice (6-8 weeks) intracranially implanted with CCDC6-RET tumors into the brain[1]
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Dosage:10 and 30 mg/kg
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Administration:p.o., BID for 90 days
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Result:Significantly prolonged the survival time and demonstrated a 100% survival rate at a dose of 10 mg/kg.
Induced complete regression of brain tumors at 10 and 30 mg/kg.
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Animal Model:Female BALB/c nude mice (6-8 weeks) subcutaneously injected with Ba/F3 KIF5B-RET G810R cells[1]
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Dosage:10 and 30 mg/kg
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Administration:p.o., BID for 15 days
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Result:Induced potent tumor growth inhibition with a TGI of 90% at 30 mg/kg, while Selpercatinib achieved only 48% TGI at the same dose.
Exhibited greater efficacy than Selpercatinib in slowing the growth of Ba/F3 KIF5B-RET G810R allograft tumors at the same dose.
Exhibited excellent tolerability at 10 and 30 mg/kg, with no significant body weight loss or apparent abnormalities in mice.
Significantly reduced tumor volume compared to control on day 11.
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Animal Model:Female BALB/c nude mice (6-8 weeks) subcutaneously injected with Ba/F3 KIF5B-RET V804M cells[1]
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Dosage:10 mg/kg
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Administration:p.o., BID for 14 days
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Result:Achieved considerably higher TGI rates of 61% compared to Selpercatinib (10 mg/kg, p.o., BID; TGI = 48%).
Was well-tolerated with no significant body weight loss in mice compared to the vehicle group during the treatment period.
| NCT Number | Sponsor | Condition | Start Date |
Phase
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|---|---|---|---|---|
| NCT01329991 | Plexxikon| | 2011-05 | PHASE1 |
Chemical Information
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CAS No. 2598870-24-5
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Appearance Solid
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분자량 496.56
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화학식 C27H28N8O2
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Color White to off-white
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SMILES
CCOC1=CN2NC3=NN=CC3=C2C(C4=CC=C(N5CC6N(C(C6)C5)CC7=CN=C(C=C7)OC)N=C4)=C1
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선적
Room temperature in continental US; may vary elsewhere.
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보관
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month
용액&용해도
DMSO : 100 mg/mL (201.39 mM; Need ultrasonic; Hygroscopic DMSO has a significant impact on the solubility of product, please use newly opened DMSO)
Please refer to the solubility information to select the appropriate solvent. Once prepared, please aliquot and store the solution to prevent product inactivation from repeated freeze-thaw cycles.
Storage method and period of stock solution: -80°C, 6 months; -20°C, 1 month. When stored at -80°C, please use it within 6 months. When stored at -20°C, please use it within 1 month.
Please refer to the solubility information to select the appropriate solvent. Once prepared, please aliquot and store the solution to prevent product inactivation from repeated freeze-thaw cycles.
Storage method and period of stock solution: -80°C, 6 months; -20°C, 1 month. When stored at -80°C, please use it within 6 months. When stored at -20°C, please use it within 1 month.
Concentration (start) × Volume (start) = Concentration (final) × Volume (final)
Select the appropriate dissolution method based on your experimental animal and administration route.
- For the following dissolution methods, please ensure to first prepare a clear stock solution using an In Vitro approach and then sequentially add co-solvents:
- To ensure reliable experimental results, the clarified stock solution can be appropriately stored based on storage conditions. As for the working solution for In Vivo experiments, it is recommended to prepare freshly and use it on the same day.
- The percentages shown for the solvents indicate their volumetric ratio in the final prepared solution. If precipitation or phase separation occurs during preparation, heat and/or sonication can be used to aid dissolution.
Add each solvent one by one: 10% DMSO 40% PEG300 5% Tween-80 45% Saline
Solubility: ≥ 2.5 mg/mL (5.03 mM); Clear solution
This protocol yields a clear solution of ≥ 2.5 mg/mL (saturation unknown).
Taking 1 mL working solution as an example, add 100 μL DMSO stock solution (25.0 mg/mL) to 400 μL PEG300, and mix evenly; then add 50 μL Tween-80 and mix evenly; then add 450 μL Saline to adjust the volume to 1 mL.
Preparation of Saline: Dissolve 0.9 g sodium chloride in ddH₂O and dilute to 100 mL to obtain a clear Saline solution.
Add each solvent one by one: 10% DMSO 90% (20% SBE-β-CD in Saline)
Solubility: ≥ 2.5 mg/mL (5.03 mM); Clear solution
This protocol yields a clear solution of ≥ 2.5 mg/mL (saturation unknown).
Taking 1 mL working solution as an example, add 100 μL DMSO stock solution (25.0 mg/mL) to 900 μL 20% SBE-β-CD in Saline, and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C, storage for one week): 2 g SBE-β-CD powder is dissolved in 10 mL Saline, completely dissolve until clear.
Please enter the basic information of animal experiments:
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Recommended: Prepare an additional quantity of animals to account for potential losses during experiments.
Please enter your animal formula composition:
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%DMSO +
Recommended: Keep the proportion of DMSO in working solution below 2% if your animal is weak.
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%+
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+%Tween-80 + +
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%Saline +
The co-solvents required include: DMSO, . All of co-solvents are available by MedChemExpress (MCE). , Tween 80. All of co-solvents are available by MedChemExpress (MCE).
Working solution concentration: 0.22 mg/mL
Method for preparing stock solution: mg drug dissolved in μL DMSO. Stock solution concentration: mg/mL.
1. Take μL DMSO stock solution;
2. Add μL .
μL , mix evenly;
3. Then add μL Tween 80, mix evenly;
4. Then add μL
Please ensure that the stock solution in the first step is dissolved to a clear state, and add co-solvents in sequence. You can use ultrasonic heating (ultrasonic cleaner, recommended frequency 20-40 kHz), vortexing, etc. to assist dissolution.
순도&문서
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Data Sheet (285 KB)
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SDS (252 KB)
- English - EN (252 KB)
- Français - FR (252 KB)
- Deutsch - DE (252 KB)
- Norwegian - NO (252 KB)
- Español - ES (252 KB)
- Swedish - SV (252 KB)
- Italian - IT (252 KB)
- Korean - KR (252 KB)
- Portuguese - PT (252 KB)
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Handling Instructions (2659 KB)
References
Complete Stock Solution Preparation Table
Please refer to the solubility information to select the appropriate solvent. Once prepared, please aliquot and store the solution to prevent product inactivation from repeated freeze-thaw cycles.
Storage method and period of stock solution: -80°C, 6 months; -20°C, 1 month. When stored at -80°C, please use it within 6 months. When stored at -20°C, please use it within 1 month.
| Optional Solvent | Concentration Solvent Mass | 1 mg | 5 mg | 10 mg | 25 mg |
|---|---|---|---|---|---|
| DMSO | 1 mM | 2.0139 mL | 10.0693 mL | 20.1386 mL | 50.3464 mL |
| 5 mM | 0.4028 mL | 2.0139 mL | 4.0277 mL | 10.0693 mL | |
| 10 mM | 0.2014 mL | 1.0069 mL | 2.0139 mL | 5.0346 mL | |
| 15 mM | 0.1343 mL | 0.6713 mL | 1.3426 mL | 3.3564 mL | |
| 20 mM | 0.1007 mL | 0.5035 mL | 1.0069 mL | 2.5173 mL | |
| 25 mM | 0.0806 mL | 0.4028 mL | 0.8055 mL | 2.0139 mL | |
| 30 mM | 0.0671 mL | 0.3356 mL | 0.6713 mL | 1.6782 mL | |
| 40 mM | 0.0503 mL | 0.2517 mL | 0.5035 mL | 1.2587 mL | |
| 50 mM | 0.0403 mL | 0.2014 mL | 0.4028 mL | 1.0069 mL | |
| 60 mM | 0.0336 mL | 0.1678 mL | 0.3356 mL | 0.8391 mL | |
| 80 mM | 0.0252 mL | 0.1259 mL | 0.2517 mL | 0.6293 mL | |
| 100 mM | 0.0201 mL | 0.1007 mL | 0.2014 mL | 0.5035 mL |
APS03118 Related Classifications
HY-178061 Related Classifications
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