PTC-003
PTC-003 is an orally active and blood-brain barrier-penetrant MAPT pre-mRNA splicing modulator. PTC-003 promotes skipping of exon 10 of the MAPT gene, shifting the protein isoform balance from toxic 4R-tau toward 3R-tau. PTC-003 reduces the accumulation of hyperphosphorylated tau, oligomeric tau, and insoluble tau protein. PTC-003 protects neurons from glutamate-induced neuronal stress injury, and in humanized MAPT gene-replaced N279K mice, it corrects the 3R/4R-tau isoform ratio in brain tissue and reduces the level of pathogenic pTau T231. PTC-003 can be used in research related to neurodegenerative diseases.
For research use only. We do not sell to patients.
- CAS No.: 3025238-91-6
- Formula: C18H17Cl2N3OS
- Molecular Weight:394.32
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Storage:
Please store the product under the recommended conditions in the Certificate of Analysis.
All DNA/RNA Synthesis Isoforms
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Biological Activity
Description
In Vitro
PTC-003 promotes MAPT exon 10 skipping in HEK293T-MAPT minigene cells with an EC2X of 5.2 nM; it increases endogenous 3R tau protein in U-87 human glioma cells with an EC1.3X of 7.4 nM[1].
PTC-003 (0.1-1000 nM; 24 h) decreases 4R tau in WT and tau-P301L iPSC-derived neurons differentiated for 8 weeks, and Western blot detects a corresponding increase in 3R tau in P301L neurons but not in WT neurons[1].
PTC-003 (1-1000 nM; 96 h-3 weeks) reduces 4R MAPT mRNA in tau-P301L and tau-S305N iPSC-derived neurons[1].
PTC-003 (0.1-1000 nM (P301L); 1-10000 nM (S305N); 96 h-3 weeks) reduces 4R tau protein in tau-P301L and tau-S305N iPSC-derived neurons, with P301L EC50 = 30.2-83.6 nM and S305N EC50 = 166.6-173.0 nM at 3 weeks; it reduces total tau and multiple pTau species[1].
PTC-003 treatment reduces insoluble oligomeric pTau S396 in both P301L and S305N FTD iPSC neurons, rescues glutamate-induced neuronal death, and does not alter glutamate receptor protein expression[1].
PTC-003 (1-10 μM; 96 h) does not reduce neuronal viability and increases viability in tau-S305N iPSC-derived neurons[1].
PTC-003 (0.1-1 μM; 78 h preincubation; 10 mM glutamate; 18 h) protects tau-P301L and tau-S305N iPSC-derived neurons from glutamate-induced loss of viability[1].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Cell Line:WT and tau-P301L iPSC-derived neurons
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Concentration:0.1, 1, 10, 100, 1000 nM
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Incubation Time:24 h
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Result:Reduced 4R tau in 8-week differentiated WT and tau-P301L iPSC-derived neurons, with a reciprocal 3R tau increase detected in P301L neurons but not in WT neurons by Western blot.
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Cell Line:tau-P301L and tau-S305N iPSC-derived neurons
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Concentration:0.1, 1 μM
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Incubation Time:78 h pre-incubation; 10 mM glutamate; 18 h
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Result:Protected tau-P301L and tau-S305N iPSC-derived neurons from glutamate-induced loss of viability, with ~90% and ~100% viability at 1 μM, respectively.
In Vivo
PTC-003 (1-2.5 mg/kg; p.o.; once daily; 21 days) increases the 3R tau/total tau ratio and decreases pTau T231 in the brain of N279K/N279K mice[1].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:homozygous MAPT-GR*N279K/N279K (H1 haplotype, murine Mapt-null background; 2 months old)[1]
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Dosage:7 mg/kg
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Administration:p.o.; single dose
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Result:PTC-003 and ABT coadministration enhanced brain exposure and produced an increase in the 3R/4R MAPT ratio, peaking at 16 hours postdosing.
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Animal Model:homozygous MAPT-GR*N279K/N279K (H1 haplotype, murine Mapt-null background; 2 months old)[1]
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Dosage:1 or 2.5 mg/kg
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Administration:p.o.; once daily; 21 days
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Result:Produced a dose-dependent increase in the 3R tau/total tau ratio, with 2.5 mg/kg producing a shift toward the physiological balance seen in WT mice.
Total tau was not affected by PTC-003 across any dose group.
Reduced pTau T231 in a dose-dependent manner, with 2.5 mg/kg producing the greatest reduction.
Overall, oral PTC-003 promoted MAPT E10 exclusion, increased 3R tau protein in the brain, and reduced pTau T231 accumulation.
Chemical Information
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CAS No. 3025238-91-6
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Molecular Weight 394.32
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Formula C18H17Cl2N3OS
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SMILES
ClC1=CC(NCC2=CC=CO2)=C3C(C(Cl)=C([C@H]4CC=CC[C@@H]4N)S3)=N1
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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)