2. PROTAC Protein Tyrosine Kinase/RTK Vitamin D Related/Nuclear Receptor Apoptosis
  3. PROTACs Src Estrogen Receptor/ERR Apoptosis
  4. BY13

BY13 是一种 SRC-3 PROTAC 降解剂，其 DC50 为 0.031 μM。BY13 通过下调 ERα 水平选择性阻断 ER 信号通路，其高于对雄激素受体 (AR) 的选择性。BY13 通过诱导细胞周期停滞于 G1 期并诱导细胞凋亡 (apoptosis)，有效克服乳腺癌的内分泌耐药性，其作用优于 Fulvestrant (HY-13636)。BY13 显著抑制 LCC2 异种移植小鼠模型中耐药乳腺肿瘤的生长，且无明显毒性。粉色：SRC-3 ligand (SI-2) (HY-101447)；蓝色：CRBN ligase ligand (HY-41547)；黑色：linker (HY-176226)

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BY13

BY13 Chemical Structure

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BY13 相关抗体

Top Publications Citing Use of Products

查看 PROTACs 亚型特异性产品:

查看所有亚型
von Hippel-Lindau (VHL) Cereblon MDM2 cIAP1

查看 Src 亚型特异性产品:

查看所有亚型
Lck Fyn Blk Hck Lyn Yes SRC-3

查看 Estrogen Receptor/ERR 亚型特异性产品:

查看所有亚型
Estrogen receptor ERα ERβ ERRα ERRβ ERRγ

  • 生物活性

  • 纯度 & 产品资料

  • 参考文献

生物活性

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[1]. Pink: SRC-3 ligand (SI-2) (HY-101447); Blue: CRBN ligase ligand (HY-41547); Black: linker (HY-176226)

IC50 & Target

ERα

 

SRC-3

0.031 μM (DC50)

体外研究
(In Vitro)

BY13 (0.1-10 μM，24 小时) 剂量依赖性地降低 MCF-7 细胞中的 SRC-3 和 ERα 蛋白水平，分别降解 71% 和 85%[1]。
BY13 (0.01-10 μM，36 小时) 有效抑制野生型、突变型和耐药型乳腺癌细胞的增殖 (对 MCF-7、LCC2 和 MCF-7D538G/Y537S/EGFR 细胞的 IC50 为 0.003-0.35 μM)，并以剂量依赖性方式降解突变型细胞中的 SRC-3 和 ERα (尤其是在 MCF-7Y537S 细胞中 (0.1 μM))[1]。
BY13 (0.1-10 μM，3-48 小时) 有效降低 LCC2 细胞中 SRC-3 和 ERα 蛋白水平，其效果优于 Fulvestrant (HY-13636)，并在 36 小时后达到最大降解，且几乎不再随时间增加[1]。
BY13 (0.01-20 μM，36 小时) 显著降低 MCF-7 细胞中 SRC-3 (仅 0.1 μM) 和 ERα (仅 1 μM) 的蛋白水平 (SRC-3 的 DC50 为 0.031 μM)，且对 SRC-1 亚型选择性优于 SRC-2[1]。
BY13 (0.01-5 μM，24 小时) 下调了 MCF-7 细胞中 AR 的蛋白水平，但这种作用比 ERα 弱，并且中度抑制 LNCaP 细胞中 AR 过表达 (IC50：1.43 μM)[1]。
BY13 (1 μM，36 小时) 通过泛素蛋白酶体系统 (UPS) 通路显著降低 MCF-7 细胞中 SRC-3 蛋白水平 (在 LCC2 细胞中观察到类似现象)[1]。
BY13 (1 μM，6 小时，40-76℃) 可以进入肿瘤细胞并直接与 SRC-3 结合，显著增强 MCF-7 细胞中 SRC-3 蛋白在高温下的热稳定性[1]。
BY13 (10 μM，6 小时) 诱导 MCF-7 细胞中 SRC-3 和 CRBN 的空间接近，进而促进 SRC-3-BY13-CRBN 三元复合物的形成[1]。
BY13 (0.01-10 μM，36小时) 随着浓度增加，显著增加 LCC2 细胞中 SRC-3 的 mRNA 表达，并有效降低 ERα 的 mRNA 水平[1]。
BY13 (1-20 μM，48小时) 显著诱导乳腺癌细胞凋亡，增强 MCF-7 和 LCC2 细胞的早期和晚期凋亡。
BY13 (5-20 μM，48小时) 剂量依赖性地将 LCC2 细胞阻滞于G1期，且细胞比例明显高于 S 期。
BY13 (0.01-100 μM) 具有足够的代谢稳定性和可接受的安全性，对 CYP3A4 和 hERG 通道的 IC50 分别为 2.73 和 1.1 μM。

MCE has not independently confirmed the accuracy of these methods. They are for reference only.

BY13 相关抗体:

Western Blot Analysis[1]

Cell Line: MCF-7 cells, LCC2 cells
Concentration: 0.01, 0.1, 1, 5, 10 μM
Incubation Time: 24 h
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

Western Blot Analysis[1]

Cell Line: MCF-7 cells, LCC2 cells
Concentration: 1 μM
Incubation Time: MCF-7 cells (3, 6, 9, 12, 24, 36 h), LCC2 cells (3, 6, 9, 12, 24, 36, 48 h)
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.

Western Blot Analysis[1]

Cell Line: MCF-7 cells, LCC2 cells
Concentration: 1 μM after 1 μM of MG-132, Bortezomib, Chloroquine or (BY13-Neg, SI-2 and Pomalidomide) for 2 h
Incubation Time: 36 h
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).

Apoptosis Analysis[1]

Cell Line: MCF-7 cells, LCC2 cells
Concentration: 1, 5, 10, 20 μM
Incubation Time: 48 h
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.
药代动力学
(Parmacokinetics)
Species Dose SampleTime Route Indicator value
Mice 2 mg/kg 0.167, 0.333, 0.5, 0.75, 1, 2, 3, 6, 9, 24, 48 h i.v. T1/2 3.44 hr
Mice 20 mg/kg 0.167, 0.333, 0.5, 0.75, 1, 2, 3, 6, 9, 24, 48 h p.o. T1/2 4.49 hr
Mice 4 mg/kg 0.167, 0.333, 0.5, 0.75, 1, 2, 3, 6, 9, 24, 48 h i.p. T1/2 3.46 hr
Mice 2 mg/kg 0.167, 0.333, 0.5, 0.75, 1, 2, 3, 6, 9, 24, 48 h i.v. Cmax 147.85 ng/mL
Mice 20 mg/kg 0.167, 0.333, 0.5, 0.75, 1, 2, 3, 6, 9, 24, 48 h p.o. Tmax 0.33 hr
Mice 4 mg/kg 0.167, 0.333, 0.5, 0.75, 1, 2, 3, 6, 9, 24, 48 h i.p. Tmax 0.33 hr
Mice 2 mg/kg 0.167, 0.333, 0.5, 0.75, 1, 2, 3, 6, 9, 24, 48 h i.v. AUC0-t 318.39 ng·h/mL
Mice 20 mg/kg 0.167, 0.333, 0.5, 0.75, 1, 2, 3, 6, 9, 24, 48 h p.o. Cmax 25.44 ng/mL
Mice 4 mg/kg 0.167, 0.333, 0.5, 0.75, 1, 2, 3, 6, 9, 24, 48 h i.p. Cmax 31.19 ng/mL
Mice 2 mg/kg 0.167, 0.333, 0.5, 0.75, 1, 2, 3, 6, 9, 24, 48 h i.v. AUC0-∞ 367.1 ng·h/mL
Mice 20 mg/kg 0.167, 0.333, 0.5, 0.75, 1, 2, 3, 6, 9, 24, 48 h p.o. AUC0-t 47.07 ng·h/mL
Mice 4 mg/kg 0.167, 0.333, 0.5, 0.75, 1, 2, 3, 6, 9, 24, 48 h i.p. AUC0-t 49.14 ng·h/mL
Mice 20 mg/kg 0.167, 0.333, 0.5, 0.75, 1, 2, 3, 6, 9, 24, 48 h p.o. AUC0-∞ 58.39 ng·h/mL
Mice 4 mg/kg 0.167, 0.333, 0.5, 0.75, 1, 2, 3, 6, 9, 24, 48 h i.p. AUC0-∞ 55.19 ng·h/mL
体内研究
(In Vivo)

BY13 (3-10 μM/kg，腹腔注射，每两天一次，共 23 天) 通过靶向 SRC-3 和 ERα 降解，在 LCC2 异种移植小鼠模型中发挥强效的抗内分泌抗性活性，其安全性高，并且改善了内分泌抗性乳腺癌的不良预后[1]。

MCE has not independently confirmed the accuracy of these methods. They are for reference only.

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].
Dosage: 3, 5 10 μM/kg, Tamoxifen (10 μM/kg) and Fulvestrant (5 μM/kg)
Administration: i.p., once every two days for 23  days after tumors reached approximately 100 mm3, and then collected sample at 36 day1.
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.
分子量

645.71

Formula

C35H35N9O4
运输条件

Room temperature in continental US; may vary elsewhere.
储存方式

Please store the product under the recommended conditions in the Certificate of Analysis.
纯度 & 产品资料
参考文献

BY13 相关分类

  • 摩尔计算器

  • 稀释计算器

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质量   浓度   体积   分子量 *
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Help & FAQs
  • Do most proteins show cross-species activity?

    Species cross-reactivity must be investigated individually for each product. Many human cytokines will produce a nice response in mouse cell lines, and many mouse proteins will show activity on human cells. Other proteins may have a lower specific activity when used in the opposite species.

Keywords:

BY13BY 13BY-13PROTACsSrcEstrogen Receptor/ERRApoptosisPROTACDegradationSRC-3ERαAntidrug-resistant breast cancer activitiesMCF-7 cellsLCC2 cellsLCC2 xenograft mice modelInhibitorinhibitorinhibit

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