2. PROTAC Epigenetics
  3. PROTACs Epigenetic Reader Domain
  4. LJM133

LJM133 是一种靶向 SMARCA2/PBRM1/SMARCA4 的 PROTAC 降解剂，其 DC50 值分别为 3.5 nM、7 nM 和 6.4 nM。LJM133 可与 VHL E3 连接酶形成三元复合物，从而驱动靶蛋白通过蛋白酶体介导的途径降解。LJM133 能够抑制细胞增殖，并在 SMARCA4 突变型癌症异种移植模型中展现出显著的抗肿瘤活性。LJM133 可用于癌症相关研究，例如 SMARCA4 突变型非小细胞肺癌研究。

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LJM133

LJM133 Chemical Structure

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LJM133 相关抗体

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von Hippel-Lindau (VHL) Cereblon MDM2 cIAP1

  • 生物活性

  • 纯度 & 产品资料

  • 参考文献

生物活性

LJM133 is a SMARCA2/PBRM1/SMARCA4 PROTAC degrader with DC50 values of 3.5 nM, 7 nM, and 6.4 nM. LJM133 induces ternary complex formation with VHL E3 ligase to drive proteasome-mediated degradation of target proteins. LJM133 suppresses cell proliferation and exhibits significant antitumor efficacy in a SMARCA4 mutant cancer xenograft model. LJM133 can be used for the research of cancer, such as SMARCA4 mutant non-small cell lung cancer[1].

IC50 & Target[1]

VHL

 

SMARCA2

3.5 nM ()

SMARCA4

6.4 nM ()

PBRM1

7 nM ()

体外研究
(In Vitro)

LJM133 (Compound 14) 可强效结合纯化的 SMARCA2BD (IC50 = 79.7 nM)、SMARCA4BD (IC50 = 369.5 nM) 及 PBRM1BD5 (IC50 = 12.1 nM)[1]。
LJM133 (5 days) 可强效抑制 NCI-H1944 细胞与 NCI-H1568 细胞的增殖，其对两种细胞的 IC50 分别为 18 nM 和 23 nM[1]。
LJM133 (1-100 nM; 2 h) 可降解 NCI-H1944 细胞中的 SMARCA2，其 DC50 为 8.6 nM[1]。
LJM133 (0.1-300 nM; 2 h) 可在 NCI-H1975 细胞中降解 SMARCA2 (DC50 = 3.5 nM)、SMARCA4 (DC50 = 7.0 nM) 和 PBRM1 (DC50 = 6.4 nM)[1]。
LJM133 (30 nM; 2 h) 可通过依赖靶标结合及功能性 VHL E3 连接酶活性的经典 PROTAC 机制，诱导 NCI-H1568 细胞中 SMARCA2 和 PBRM1 发生蛋白酶体依赖性降解[1]。
LJM133 (0-24 h) 可诱导 NCI-H1944 细胞中 SMARCA2 和 PBRM1 快速降解，且在 2 h 内达到最大耗竭水平[1]。
LJM133 (1-100 nM; 18 h) 可在 NCI-H1944 细胞中以剂量依赖方式下调 KRT80 和 PLAU 的 mRNA 水平[1]。

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

LJM133 相关抗体:

Western Blot Analysis[1]

Cell Line: NCI-H1944 SMARCA4-mutant nonsmall cell lung cancer cells
Concentration: 1, 3, 10, 30, 100 nM
Incubation Time: 2 h
Result: Induced robust degradation of SMARCA2, with a DC50 of 8.6 nM.

Western Blot Analysis[1]

Cell Line: NCI-H1975 SMARCA4 wild-type nonsmall cell lung cancer cells
Concentration: 0.1, 0.3, 1, 3, 10, 30, 300 nM
Incubation Time: 2 h
Result: Induced degradation of SMARCA2 with a DC50 of 3.5 nM.
Induced degradation of SMARCA4 with a DC50 of 7.0 nM.
Induced degradation of PBRM1 with a DC50 of 6.4 nM.

Western Blot Analysis[1]

Cell Line: NCI-H1568 SMARCA4-mutant nonsmall cell lung cancer cells
Concentration: 30 nM
Incubation Time: 2 h
Result: Rescued degradation of SMARCA2 and PBRM1 induced by LJM133 via pretreatment with proteasome inhibitor MG132 (HY-13259), cullin-RING E3 ligase inhibitor MLN4924 (HY-70062), SMARCA2/4/PBRM1 ligand 4p (HY-182987), or VHL-binding competitor ARV-056.
Failed to rescue degradation via pretreatment with lysosome inhibitor Chloroquine (HY-17589A).

Real Time qPCR[1]

Cell Line: NCI-H1944 SMARCA4-mutant nonsmall cell lung cancer cells
Concentration: 1, 10, 100 nM
Incubation Time: 18 h
Result: Induced a dose-dependent reduction in mRNA levels of SMARCA2 target genes KRT80 and PLAU, with significant decreases observed at concentrations ≥10 nM.
药代动力学
(Parmacokinetics)
Species Dose Route T1/2 Cmax AUC0-t Bioavailability C0 Vz CL AUC
Mice[1] 5 mg/kg i.v. 7.06 h / 12400 ng·h/mL / 7318 ng/mL 3.83 L/kg 6.27 mL/min/kg /
Mice[1] 15 mg/kg i.p. 18.85 h 2386 ng/mL 24391 ng·h/mL 65.5 % / / / /
Mice[1] 15 mg/kg p.o. 0.97 h 18 ng/mL 30 ng·h/mL 0.08 % / / / /
Rat[1] 5 mg/kg i.v. / / / / 6770 ng/mL / / 1667 ng·h/mL
Rat[1] 15 mg/kg i.p. / 672 ng/mL / 33 % / / / 2048 ng·h/mL
体内研究
(In Vivo)

LJM133 (Compound 14) (50 mg/kg；静脉注射；单次给药) 可在体内实现持久的靶点结合，能在 NCI-H1944 异种移植肿瘤中诱导 SMARCA2 和 PBRM1 发生显著降解，持续时间长达 48 小时[1]。
LJM133 (25-50 mg/kg；静脉注射；每周 3 次；持续 18 天) 在 NCI-H1944 异种移植模型中展现出显著的、剂量依赖性抗肿瘤功效[1]。

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

Animal Model: BALB/c nude mice with NCI-H1944 xenograft harboring a mutation in SMARCA4[1]
Dosage: 50 mg/kg
Administration: i.v.; single dose
Result: Induced robust degradation of SMARCA2 and PBRM1 in tumor tissues at 4 and 24 hours post-dose, with partial recovery detected at 48 hours.
Reached plasma concentrations of 3.9 μM at 4 hours, 0.6 μM at 24 hours, and 0.3 μM at 48 hours.
Achieved corresponding tumor concentrations of 1.6 μM at 4 hours, 0.5 μM at 24 hours, and 0.3 μM at 48 hours.
Animal Model: BALB/c nude mice with NCI-H1944 xenograft harboring a mutation in SMARCA4[1]
Dosage: 25 mg/kg; 50 mg/kg
Administration: i.v.; three times weekly; 18 days
Result: Induced dose-dependent tumor growth inhibition, with T/C values of 42.9% at 25 mg/kg and 24.0% at 50 mg/kg.
Achieved efficacy comparable to the reference PROTAC AU-15330 (HY-145388) at 50 mg/kg (T/C = 41.2%) at the 25 mg/kg dose.
Caused no significant body weight loss across treatment groups.
Induced near-complete degradation of SMARCA2 and PBRM1 in tumors at study termination for both 25 mg/kg and 50 mg/kg doses.
分子量

994.02

Formula

C51H58BrFN8O5S
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

LJM133 相关分类

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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:

LJM133LJM 133LJM-133PROTACsEpigenetic Reader Domainxenograft modelSMARCA2NCI-H1975 cellsSMARCA4VHL E3 ligasenon-small cell lung cancerNCI-H1568 cellsNCI-H1944 cellsPBRM1proteasomeInhibitorinhibitorinhibit

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