ERD-12310A
ERD-12310A is an orally active ERα PROTAC degrader, with a Ki value of 0.95 nM against human ERα and a DC50 of 47 pM for ERα in MCF-7 cells. ERD-12310A forms a ternary complex with ERα and the CRBN E3 ubiquitin ligase, thereby inducing ubiquitination and proteasomal degradation of wild-type and ESR1Y537S mutant ERα. ERD-12310A induces tumor regression in ER+ breast cancer xenografts and inhibits tumor growth in ESR1Y537S mutant breast cancer xenografts. ERD-12310A can be used in studies related to ER-positive breast cancer and ESR1-mutant breast cancer.
(Pink: ERα ligand (HY-164925); Blue: Cereblon ligand (HY-168055); Black: linker).
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- CAS 番号: 3026007-23-5
- 分子式: C51H56N4O6
- 分子量:821.01
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保管条件:
Please store the product under the recommended conditions in the Certificate of Analysis.
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生物活性
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化学情報
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- 純度とドキュメンテーション
- 参考文献
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生物活性
製品説明
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hERα 0.95 nM (Ki) |
ERα 47 pM (DC50) |
体外実験
ERD-12310A potently and efficiently degrades ERα in MCF-7 cells with a DC50 of 47 pM and Dmax of 103%, and is 10 times more potent than ARV-471[1][2].
ERD-12310A (0.3-10 nM; 4 h) potently degrades ERα in MCF-7 and T47D cells, achieving maximum degradation at 1 nM (4 h) in MCF-7 cells and 10 nM (4 h) in T47D cells[2].
ERD-12310A (10-100 nM; 7 h) degrades >80% of wild-type, ERαY537S mutant, and ERαD538G mutant ERα protein in MCF-7 cell lines at 10 nM and 100 nM following a 7 h treatment, with degradation dependent on cereblon binding[2].
ERD-12310A (5 nM; 4 h, with 2 h pretreatment of blocking agents) mediated ERα degradation in MCF-7 cells requires binding to ERα and cereblon, and is dependent on neddylation and proteasome activity[2].
ERD-12310A (0.5-500 nM; 5 h) does not significantly degrade the neo-substrate GSPT1 in MCF-7 cells at concentrations from 0.5 nM to 500 nM over 5 h, despite potently degrading ERα[2].
ERD-12310A (range of concentrations) potently inhibits MCF-7 cell growth, with activity primarily driven by ERα degradation, and shows a hook effect at 1 μM[2].
ERD-12310A binds to purified human ERα protein with a Ki of 0.95 nM[2].
ERD-12310A (1 μM; 0-60 min) has excellent stability in human, rat, and mouse liver microsomes, with a T1/2 of >60 min across all species[2].
ERD-12310A weakly inhibits most human CYP isoforms (IC50 >10 μM) and moderately inhibits CYP2B6 (IC50 = 2.5 μM) and CYP2C19 (IC50 = 6.0 μM)[2].
ERD-12310A (range of concentrations) is a very weak hERG channel inhibitor, with IC50 >10 μM and 43.7% inhibition observed at 10 μM[2].
ERD-12310A exhibits high plasma protein binding, with 98.9%, 95.7%, and 99.0% bound in human, rat, and mouse plasma, respectively[2].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only. Further protocols information, click here.
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Cell Line:ER+ MCF-7 and T47D human breast cancer cell lines
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Concentration:0.3 nM (MCF-7); 1 nM (MCF-7); 3 nM (T47D); 10 nM (T47D)
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Incubation Time:4 h
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Result:Reduced ERα protein levels at 0.3 nM and achieved maximum degradation at 1 nM with a 4 h treatment in MCF-7 cells.
Significantly reduced ERα protein levels at 3 nM and achieved maximum degradation at 10 nM with a 4 h treatment in T47D cells.
Was 3-10 times more potent than ARV-471 in both cell lines.
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Cell Line:ER+ wild-type MCF-7, MCF-7 Y537S mutant, and MCF-7 D538G mutant human breast cancer cell lines
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Concentration:10 nM; 100 nM
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Incubation Time:7 h
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Result:Reduced wild-type ERα protein levels by >80% at both 10 nM and 100 nM with a 7 h treatment.
Reduced Y537S and D538G mutant ERα protein levels by >80% at both 10 nM and 100 nM with a 7 h treatment.
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Cell Line:ER+ MCF-7 human breast cancer cell line
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Concentration:0.5 nM; 5 nM; 50 nM; 500 nM
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Incubation Time:5 h
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Result:Showed minimal effect on GSPT1 protein levels across all tested concentrations.
Potently degraded ERα protein levels in a dose-dependent manner.
Control GSPT1 degrader MG-277 effectively reduced GSPT1 levels but had no effect on ERα.
Parmacokinetics
| Species | Dose | Route | Vss | CL | AUC0-∞ | Cmax | T1/2 | F |
|---|---|---|---|---|---|---|---|---|
| Mice[2] | 1 mg/kg | i.v. | 5.8 L/kg | 18.8 mL/min/kg | / | / | / | / |
| Mice[2] | 3 mg/kg | p.o. | / | / | 979 ng·h/mL | 58.6 ng/mL | 13.3 h | 37 % |
| Rat[2] | 1 mg/kg | i.v. | 1.9 L/kg | 9.7 mL/min/kg | / | / | / | / |
| Rat[2] | 3 mg/kg | p.o. | / | / | 583 ng·h/mL | 57.7 ng/mL | 5.6 h | 10 % |
| Dog[2] | 1 mg/kg | i.v. | 3.2 L/kg | 2.1 mL/min/kg | / | / | / | / |
| Dog[2] | 3 mg/kg | p.o. | / | / | 15118 ng·h/mL | 469.4 ng/mL | 23.2 h | 49 % |
体内実験
ERD-12310A (5-30 mg/kg; p.o.; 5 days a week; 5 weeks) achieves strong tumor growth inhibition (75% TGI at 10 mg/kg) and complete tumor growth inhibition at an escalated dose in the MCF-7 ESR1Y537S mutant ER xenograft model following 5 weeks of intermittent daily oral administration[2].
ERD-12310A (10-30 mg/kg; p.o.; daily; 3 days) achieves sustained reduction of wild-type ER protein (66-72% depletion) in MCF-7 xenograft tumors 24 hours after 3 days of daily oral administration at 10-30 mg/kg[2].
ERD-12310A (10-30 mg/kg; p.o.; single dose; daily; 3 days) achieves significant depletion of ESR1Y537S mutant ER protein (71-74% reduction) in MCF-7 xenograft tumors 24 hours after a single 10 mg/kg oral dose or 3 days of daily oral dosing at 10-30 mg/kg[2].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:SCID mice[2]
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Dosage:3 mg/kg; 10 mg/kg; 30 mg/kg
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Administration:p.o.; daily; 5 weeks
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Result:Achieved 93% tumor growth inhibition (TGI).
Achieved 94% TGI.
Achieved tumor regression with 110% TGI at the end of treatment (day 81).
Caused no significant weight loss or toxicity symptoms throughout the experiment.
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Animal Model:SCID mice[2]
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Dosage:10 mg/kg; 5 mg/kg (for 3 weeks) followed by 30 mg/kg (for 2 weeks)
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Administration:p.o.; 5 days a week; 5 weeks
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Result:Achieved 75% TGI after 5 weeks of treatment at 10 mg/kg.
Completely inhibited tumor growth during the treatment period at the escalated dose (5 mg/kg for 3 weeks, then 30 mg/kg for 2 weeks).
Caused no significant weight loss or toxicity symptoms throughout the experiment.
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Animal Model:SCID mice[2]
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Dosage:10 mg/kg; 30 mg/kg
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Administration:p.o.; daily; 3 days
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Result:Reduced wild-type ER protein levels by 69% in tumor tissue at 10 mg/kg at the 24-hour time point after the last dose.
Reduced wild-type ER protein levels by 72% in tumor tissue at 30 mg/kg at the 24-hour time point after the last dose.
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Animal Model:SCID mice[2]
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Dosage:10 mg/kg (single dose); 10 mg/kg (daily for 3 days); 30 mg/kg (daily for 3 days)
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Administration:p.o.; single dose; daily; 3 days
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Result:Reduced ESR1Y537S protein levels by 71% in tumor tissue at 24 hours after a single 10 mg/kg dose.
Reduced ESR1Y537S protein levels by 74% in tumor tissue at 24 hours after the last dose of daily 10 mg/kg dosing for 3 days.
Reduced ESR1Y537S protein levels by 74% in tumor tissue at 24 hours after the last dose of daily 30 mg/kg dosing for 3 days.
化学情報
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CAS 番号 3026007-23-5
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分子量 821.01
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分子式 C51H56N4O6
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SMILES
O=C(N1)[C@H](CCC1=O)N(C2=O)CC3=C2C=CC4=C3OCC45CCN(CC5)C[C@H]6COC7(CC6)CCN(CC7)C8=CC=C(C=C8)[C@H]9[C@H](CCC%10=C9C=CC(O)=C%10)C%11=CC=CC=C%11
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輸送条件
Room temperature in continental US; may vary elsewhere.
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保管条件
Please store the product under the recommended conditions in the Certificate of Analysis.
プロトコル
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Patient-Derived Xenograft (PDX)
Patient-derived xenograft (PDX) models are generated by engrafting primary human tumor tissue directly into immunodeficient mice, allowing in vivo propagation of patient tumor biology without initial in vitro adaptation. These models are used to preserve key histopathological and molecular characteristics of the original tumor and enable assessment of tumor growth dynamics and therapeutic response in a living organism. The biological readout is tumor engraftment and subsequent growth in the murine host, which reflects the ability of human tumor cells to survive, vascularize, and expand in an immunocompromised microenvironment.
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Patient-Derived Orthotopic Xenograft (PDOX)
Patient-derived orthotopic xenograft (PDOX) modeling implants fresh patient tumor tissue or patient-derived tumor cells into the anatomically corresponding organ or tissue site of immunodeficient mice, usually by surgical orthotopic implantation, to preserve patient tumor histology, local microenvironmental context, invasion, metastatic behavior, and treatment-response features better than subcutaneous implantation. PDOX readouts include tumor engraftment, orthotopic tumor growth, local invasion, metastasis, recurrence after resection, histologic similarity to the donor tumor, biomarker retention, molecular concordance, survival, and response or resistance to therapy. PDOX models are used for preclinical drug testing and individualized therapy evaluation, but engraftment success varies by tumor type and specimen quality.
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Subcutaneous Cell-Line-Derived Xenograft
Subcutaneous cell-line-derived xenograft (CDX) models are established by implanting cultured human cancer cell lines into immunodeficient mice, where the injected cells form localized tumors that can be monitored in vivo as a measure of tumorigenic potential, growth kinetics, and treatment response. These models are widely used in oncology research because they allow reproducible tumor formation and enable comparative assessment of tumor growth between different cell lines or genetic manipulations in a controlled in vivo microenvironment. Subcutaneous implantation of cancer cells in immunodeficient mice is a standard approach for evaluating tumor growth behavior and therapeutic response across multiple cancer types, including prostate, esophageal, pancreatic, and colon cancer models.
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Breast Cancer Modeling
Breast cancer is a heterogeneous cancer, and it has been distinguished into four subtypes: luminal A, luminal B, HER2-positive and basal-like. Molecular mutations, epigenetic alterations, hormone exposure and immune microenvironment are related to the progression of breast cancer.
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Orthotopic Cell-Line Xenograft
Orthotopic cell-line xenograft models involve implantation of human cancer cell lines into the anatomically corresponding organ of immunodeficient mice to reproduce tumor growth within a native microenvironment, enabling more clinically relevant tumor behavior compared with subcutaneous models. These models are widely used because orthotopic placement better recapitulates tumor progression, including invasion and metastatic spread, which are often underrepresented in heterotopic implantation systems. Compared with conventional xenografts, orthotopic implantation is described as more technically complex but provides improved simulation of tumor-microenvironment interactions and metastatic behavior, making it particularly valuable for translational oncology research. Surgical orthotopic implantation approaches have been emphasized as enabling faithful reproduction of clinical cancer features, including metastasis and disease progression patterns that align with the tumor’s organ of origi
純度とドキュメンテーション
参考文献
[1]. Peng R, et al. Development of PROTACs targeting estrogen receptor: an emerging technique for combating endocrine resistance. RSC medicinal chemistry. 2025 Mar 19;16(3):1023-1036. [Content Brief]
[2]. Rej RK, et al. Discovery of ERD-12310A as an Exceptionally Potent and Orally Efficacious PROTAC Degrader of Estrogen Receptor α (ERα). Journal of medicinal chemistry. 2024 Dec 12;67(23):20933-20965. [Content Brief]
Calculators
濃度 (開始) × 体積 (開始) = 濃度 (終了) × 体積 (終了)
ERD-12310A 関連分類
HY-164924 関連分類
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