BY13
BY13 is a SRC-3 PROTAC degrader with a DC50 of 0.031 μM. BY13 selectively blocks the ER signaling pathway over that of androgen receptor (AR)) through down-regulating ERα level. BY13 potently overcomes endocrine resistance in breast cancer by inducing cell cycle arrest in G1 phase and apoptosis, with superior effect over Fulvestrant (HY-13636). BY13 significantly inhibits the growth of drug-resistant breast tumors without obvious toxicity in LCC2 xenograft mice model.
(Pink: SRC-3 ligand (HY-101447); Blue: Cereblon ligand (HY-41547); Black: linker (HY-176226)).
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- Formel: C35H35N9O4
- Molecular Weight:645.71
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Speicherung:
Please store the product under the recommended conditions in the Certificate of Analysis.
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Biologische Aktivität
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ERα |
SRC-3 0.031 μM (DC50) |
BY13 (0.1-10 μM, 24 h) dose-dependently reduces SRC-3 and ERα protein level in MCF-7 cells with 71% and 85% degradation, respectively[1].
BY13 (0.01-10 μM, 36 h) potently inhibits proliferation of wild-type, mutant-type and drug-resistant breast cancer cells (IC50 of 0.003-0.35 μM for MCF-7, LCC2 and MCF-7D538G/Y537S/EGFR cells), and dose-dependently degrades SRC-3 and ERα in mutant-type cells (particularly in MCF-7Y537S cells at 0.1 μM)[1].
BY13 (0.1-10 μM, 3-48 h) effectively reduces SRC-3 and ERα protein level, superior to Fulvestrant (HY-13636), and reaches the maximal degradation after 36 h while almost no longer increase with time in LCC2 cells [1].
BY13 (0.01-20 μM, 36 h) dramatically decreases the protein level of SRC-3 (0.1 μM only) and ERα (1 μM only) (DC50 of 0.031 μM for SRC-3) with subtype selectivity favoring SRC-1 over SRC-2 in MCF-7 cells[1].
BY13 (0.01-5 μM, 24 h) down-regulates the protein level of AR while this effect is weaker compared to ERα in MCF-7 cells, and moderately inhibits AR-overexpressing LNCaP cells (IC50: 1.43 μM)[1].
BY13 (1 μM, 36 h) significantly reduces SRC-3 protein level depending on a ubiquitin proteasome system (UPS) pathway in MCF-7 cells (similar phenomena observed in LCC2 cells)[1].
BY13 (1 μM, 6 h, 40-76°C) can enter tumor cells and directly bind to SRC-3 with significantly enhancement of the SRC-3 protein thermal stability at high temperature in MCF-7 cells[1].
BY13 (10 μM, 6 h) induces the spatial proximity of SRC-3 and CRBN, followed by promoting the formation of the SRC-3-BY13-CRBN ternary complex in MCF-7 cells[1].
BY13 (0.01-10 μM, 36 h) significantly increases the mRNA expression of SRC-3 with the increasing concentrations and effectively reduces the mRNA level of ERα in LCC2 cells[1].
BY13 (1-20 μM, 48 h) significantly induces breast cancer cells apoptosis with enhancement of both early and late apoptosis in MCF-7 and LCC2 cells.
BY13 (5-20 μM, 48 h) dose-dependently arrests LCC2 cells in the G1 phase, and thecell proportion is significantly higher than that in the S phase.
BY13 (0.01-100 μM) has sufficient metabolic stability and an acceptable safety profile with IC50 of 2.73 and 1.1 μM for CYP3A4 and hERG channel.
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Cell Line:MCF-7 cells, LCC2 cells
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Concentration:0.01, 0.1, 1, 5, 10 μM
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Incubation Time:24 h
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Result:Degraded both SRC-3 and ERα protein in MCF-7 cells at 1 μM with 71% and 85% degradation, respectively.
Dose-dependently reduced SRC-3 and ERα protein level in MCF-7 cells without a canonical “hook effect” as well as significantly degrades SRC-3 and ERα in LCC2 cells, superior to Fulvestrant (HY-13636).
Down-regulated the protein level of AR while this effect is weaker compared to ERα in MCF-7 cells
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Cell Line:MCF-7 cells, LCC2 cells
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Concentration:1 μM
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Incubation Time:MCF-7 cells (3, 6, 9, 12, 24, 36 h), LCC2 cells (3, 6, 9, 12, 24, 36, 48 h)
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Result:Effectively reduced the SRC-3 protein level after 24h and reached the maximal degradation in MCF-7 cells at 36 h. Significantly reduced the protein level of SRC-3 after only 9 h of treatment, and reached the maximal degradation in LCC2 cells at 36 h with almost no longer increase of degradation.
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Cell Line:MCF-7 cells, LCC2 cells
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Concentration:1 μM after 1 μM of MG-132, Bortezomib, Chloroquine or (BY13-Neg, SI-2 and Pomalidomide) for 2 h
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Incubation Time:36 h
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Result:Significantly reduced SRC-3 protein level depending on a ubiquitin proteasome system (UPS) pathway, but this effect was reversed by two proteasome inhibitors (MG-132, Bortezomib and SI-2) not by BY13-Neg in MCF-7 cells (similar symptoms observed in LCC2 cells).
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Cell Line:MCF-7 cells, LCC2 cells
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Concentration:1, 5, 10, 20 μM
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Incubation Time:48 h
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Result:Effectively induced cell apoptosis with enhancement of both early and late apoptosis in MCF-7 cells at increased concentrations (35% maximal early apoptosis rate).
Mainly induced the late apoptosis at 1 μM, but resulted in early apoptosis at 10 μM and induced a strong early apoptotic effect at 20 μM (＞ 30% early apoptosis rate) in LCC2 cells.
| Species | Dose | Route | T1/2 | Cmax | AUC0-t | AUC0-∞ | Tmax |
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| Mice | 2 mg/kg | i.v. | 3.44 h | 147.85 ng/mL | 318.39 ng·h/mL | 367.1 ng·h/mL | / |
| Mice | 20 mg/kg | p.o. | 4.49 h | 25.44 ng/mL | 47.07 ng·h/mL | 58.39 ng·h/mL | 0.33 h |
| Mice | 4 mg/kg | i.p. | 3.46 h | 31.19 ng/mL | 49.14 ng·h/mL | 55.19 ng·h/mL | 0.33 h |
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 (4 weeks old) were injected subcutaneously into the right lower axilla with LCC2 cells (5 × 106 cells/mouse) to induce LCC2 xenograft mice model[1].
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Dosage:3, 5 10 μM/kg, Tamoxifen (10 μM/kg) and Fulvestrant (5 μM/kg)
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Administration:i.p., once every two days for 23 days after tumors reached approximately 100 mm3, and then collected sample at 36 day1.
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Result:Significantly inhibited tumor growth at 3 μM/kg, with superior effect of 54% tumor growth inhibition rate 54% at 5 μM/kg.
Almost completely degraded SRC-3 protein within the tumor tissues at 3 μM/kg, and the protein levels of both SRC-3 and ERα were further decreased at 5 μM/kg.
Had a wide therapeutic window, without effect weight gain of mice model up to 10 μM/kg.
Had a high safety property without observable histopathological changes in the organ tissues of mice model during the administration period at 3 and 5 μM/kg.
Improved the poor prognosis of endocrine-resistant breast cancer with reducement of ki67 level in tumor tissues at 3 and 5 μM/kg.
Chemical Information
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Molecular Weight 645.71
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Formel C35H35N9O4
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SMILES
C/C(C1=NC=CC=C1)=N\NC2=NC(C=CC=C3)=C3N2C4CN(C4)C5CCN(CC5)C6=CC=CC7=C6C(N(C7=O)C8C(NC(CC8)=O)=O)=O
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Versand
Room temperature in continental US; may vary elsewhere.
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Speicherung
Please store the product under the recommended conditions in the Certificate of Analysis.
Reinheit & Dokumentation
Verweise
Calculators
Konzentration (Stammlösung) × Volumen (Stammlösung) = Konzentration (Ziellösung) × Volumen (Ziellösung)
BY13 Related Classifications
HY-176225 Related Classifications
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