SMD-6346
SMD-6346 is an orally active SMARCA2 PROTAC degrader with a DC50 of 3.3 nM. SMD-6346 induces SMARCA2 degradation and exhibits extremely low activity against SMARCA4. SMD-6346 inhibits the growth of SMARCA4-deficient cancer cells and suppresses tumor growth in mouse xenograft models. SMD-6346 can be used for the research of non-small cell lung cancer.
(Pink: SMARCA2 ligand (HY-170817); Blue: Cereblon ligand (HY-W440247); Black: linker).
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- No. CAS: 3086248-19-0
- Fòrmula: C46H50ClF2N5O4
- Peso molecular:810.37
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Almacenamiento:
Please store the product under the recommended conditions in the Certificate of Analysis.
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Actividad biológica
Descripciòn
IC50 & Target
[1]|
SMARCA2 3.3 nM (DC50) |
In Vitro
SMD-6346 (24 h) potently and selectively degrades SMARCA2 (DC50 = 3.3 nM, Dmax = 91%) in CRISPR/Cas9-modified HeLa cells expressing HiBiT-tagged SMARCA2 and SMARCA4, while it exhibits much weaker degrading activity against SMARCA4 (DC50 > 1000 nM, Dmax = 46%)[1].
SMD-6346 (0.1-10000 nM; 24 h) potently induces nearly complete degradation of SMARCA2 (DC50 is 6 nM in H838 cells, 22 nM in SK-MEL-5 cells, and 11 nM in 22Rv1 cells; Dmax reaches > 95% in all three cell lines), and exhibits over 900-fold selectivity for SMARCA2 over SMARCA4 in 22Rv1 cells[1].
SMD-6346 (0-1 μM; 7 days) potently inhibits the growth of SMARCA4-deficient cancer cell lines (with a GI50 of 4.0 nM in SK-Mel-5, 19 nM in H838, and 78 nM in H1944), while it exhibits only extremely low activity in SMARCA4 wild-type cell lines (GI50 > 1000 nM)[1].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Cell Line:H838 (SMARCA4-deficient lung cancer), SK-MEL-5 (SMARCA4-deficient melanoma), 22Rv1 (SMARCA2/4 wild-type prostate cancer)
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Concentration:0.1, 0.3, 1, 3, 10, 30, 100, 300, 1000, 3000 and 10000 nM
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Incubation Time:24 h
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Result:Induced near-complete SMARCA2 degradation (Dmax > 95%) with a DC50 of 6 nM in H838 cells.
Achieved near-complete SMARCA2 degradation (Dmax > 95%) with a DC50 of 22 nM in SK-MEL-5 cells.
Potently degraded SMARCA2 (DC50 = 11 nM, Dmax > 95%) but only modestly reduced SMARCA4 levels (Dmax = 38% even at 10 μM) in 22Rv1 cells.
Resulted in a > 900-fold degradation selectivity for SMARCA2 over SMARCA4 in 22Rv1 cells.
Parmacokinetics
In Vivo
SMD-6346 (5-10 mg/kg; p.o.; administered 5 days per week for 2 consecutive weeks) inhibits tumor growth in H838 xenograft mice[1].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:CB.17 SCID (female, 6-10 weeks old)[1]
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Dosage:10 mg/kg (single dose; 3 consecutive daily doses); 30 mg/kg (single dose; 3 consecutive daily doses)
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Administration:p.o.; single dose; daily for 3 consecutive days
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Result:Reduced SMARCA2 protein to 24.5% of vehicle control levels at 24 hours after a single 10 mg/kg dose.
Reduced SMARCA2 protein to 13.1% of control at 24 hours after a single 30 mg/kg dose.
Reduced SMARCA2 protein to 28.4% of control at 3 hours and 22.4% of control at 24 hours after the final dose of three daily 10 mg/kg doses.
Reduced SMARCA2 protein to 7.8% of control at 3 hours and 7.9% of control at 24 hours after the final dose of three daily 30 mg/kg doses.
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Animal Model:CB.17 SCID (female, 6-8 weeks old)[1]
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Dosage:5 mg/kg; 10 mg/kg
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Administration:p.o.; daily 5 days per week; 2 weeks
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Result:Inhibited tumor growth by 33% after 2 weeks of treatment with 5 mg/kg dose.
Inhibited tumor growth by 59% after 2 weeks of treatment with 10 mg/kg dose.
Caused minimal weight loss with both doses, indicating good tolerability.
Chemical Information
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No. CAS 3086248-19-0
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Peso molecular 810.37
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Fòrmula C46H50ClF2N5O4
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SMILES
O=C(C(C1=C(F)C=C(N(CC2)CCC32CCC(CN4CCC(C5=CC(N6C7=NC(C8=C6C=CC=C8Cl)=O)=C(C97CCCCC9)C=C5)CC4)CO3)C=C1F)CC%10)NC%10=O
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Envío
Room temperature in continental US; may vary elsewhere.
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Almacenamiento
Please store the product under the recommended conditions in the Certificate of Analysis.
Pureza y Documentación
Referencias
Calculators
Concentration (start) × Volume (start) = Concentration (final) × Volume (final)
SMD-6346 Related Classifications
HY-184673 Related Classifications
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