LJM133
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.
(Pink: SMARCA2 and SMARCA4 and PBRM1 ligand (HY-182987); Blue: E3 ligase ligand; Black: linker).
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- Formule: C51H58BrFN8O5S
- Masse moléculaire:994.02
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Stockage:
Please store the product under the recommended conditions in the Certificate of Analysis.
To place orders, for customer services and technical support, please contact: MedChemExpress USA
Tel: 609-228-6898 E-mail: [email protected] [email protected]
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Activité biologique
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Chemical Information
- Pureté et documentation
- Références
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Activité biologique
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VHL |
SMARCA2 3.5 nM (IC50) |
SMARCA4 6.4 nM (IC50) |
PBRM1 7 nM (IC50) |
LJM133 (Compound 14) potently binds purified SMARCA2BD (IC50 = 79.7 nM), SMARCA4BD (IC50 = 369.5 nM), and PBRM1BD5 (IC50 = 12.1 nM)[1].
LJM133 (5 days) potently inhibits proliferation of NCI-H1944 cells (IC50 = 18 nM) and NCI-H1568 cells (IC50 = 23 nM)[1].
LJM133 (1-100 nM; 2 h) degrades SMARCA2 in NCI-H1944 cells with a DC50 of 8.6 nM[1].
LJM133 (0.1-300 nM; 2 h) degrades SMARCA2 (DC50 = 3.5 nM), SMARCA4 (DC50 = 7.0 nM), and PBRM1 (DC50 = 6.4 nM) in NCI-H1975 cells[1].
LJM133 (30 nM; 2 h) induces proteasome-dependent degradation of SMARCA2 and PBRM1 in NCI-H1568 cells via a canonical PROTAC mechanism requiring target engagement and functional VHL E3 ligase activity[1].
LJM133 (0-24 h) induces rapid degradation of SMARCA2 and PBRM1 in NCI-H1944 cells, with maximal depletion achieved within 2 h[1].
LJM133 (1-100 nM; 18 h) causes dose-dependent downregulation of KRT80 and PLAU mRNA levels in NCI-H1944 cells[1].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Cell Line:NCI-H1944 SMARCA4-mutant nonsmall cell lung cancer cells
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Concentration:1, 3, 10, 30, 100 nM
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Incubation Time:2 h
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Result:Induced robust degradation of SMARCA2, with a DC50 of 8.6 nM.
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Cell Line:NCI-H1975 SMARCA4 wild-type nonsmall cell lung cancer cells
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Concentration:0.1, 0.3, 1, 3, 10, 30, 300 nM
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Incubation Time:2 h
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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.
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Cell Line:NCI-H1568 SMARCA4-mutant nonsmall cell lung cancer cells
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Concentration:30 nM
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Incubation Time:2 h
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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).
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Cell Line:NCI-H1944 SMARCA4-mutant nonsmall cell lung cancer cells
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Concentration:1, 10, 100 nM
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Incubation Time:18 h
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Result:Induced a dose-dependent reduction in mRNA levels of SMARCA2 target genes KRT80 and PLAU, with significant decreases observed at concentrations ≥10 nM.
| 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 |
LJM133 (25-50 mg/kg; i.v.; three times weekly; 18 days) exhibits robust, dose-dependent antitumor efficacy in NCI-H1944 xenograft models[1].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:BALB/c nude mice with NCI-H1944 xenograft harboring a mutation in SMARCA4[1]
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Dosage:50 mg/kg
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Administration:i.v.; single dose
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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.
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Animal Model:BALB/c nude mice with NCI-H1944 xenograft harboring a mutation in SMARCA4[1]
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Dosage:25 mg/kg; 50 mg/kg
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Administration:i.v.; three times weekly; 18 days
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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.
Chemical Information
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Masse moléculaire 994.02
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Formule C51H58BrFN8O5S
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SMILES
CC1=C(SC=N1)C2=CC=C(C=C2)[C@@H](NC([C@@H]3C[C@H](CN3C([C@H](C(C)(C)C)NC(C4(CC4)F)=O)=O)O)=O)CCCCCN5CCN(CC5)C6=CC=C7C=[N+]8[N-]C(C9=C(C=CC=C9C8=CC7=C6)Br)=O
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Livraison
Room temperature in continental US; may vary elsewhere.
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Stockage
Please store the product under the recommended conditions in the Certificate of Analysis.
Pureté et documentation
Références
Calculators
Concentration (start) × Volume (start) = Concentration (final) × Volume (final)
LJM133 Related Classifications
HY-183007 Related Classifications
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