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.
For research use only. We do not sell to patients.
- CAS No.: 2598870-24-5
- Formula: C27H28N8O2
- Molecular Weight:496.56
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Storage:
Please store the product under the recommended conditions in the Certificate of Analysis.
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Biological Activity
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Chemical Information
- Purity & Documentation
- 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
|
|---|---|---|---|---|
| NCT01329991 | Plexxikon| | 2011-05 | PHASE1 |
Chemical Information
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CAS No. 2598870-24-5
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Molecular Weight 496.56
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Formula C27H28N8O2
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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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Shipping
Room temperature in continental US; may vary elsewhere.
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Storage
Please store the product under the recommended conditions in the Certificate of Analysis.
Purity & Documentation
References
Calculators
Concentration (start) × Volume (start) = Concentration (final) × Volume (final)
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