SJ11646
Based on 1 Customer Validation
SJ11646 is a LCK PROTAC degrader with a DC50 value of 0.00838 pM against LCK. SJ11646 recruits CRBN and LCK to form a ternary complex, inducing cereblon-mediated proteasomal degradation of LCK. SJ11646 induces cytotoxicity in T-ALL cells, but such cytotoxicity is reduced in cells harboring the LCKT316I mutation. SJ11646 can be used in studies related to T-cell acute lymphoblastic leukemia.
(Pink: Lck ligand (HY-107447); Blue: Cereblon ligand (HY-163169); Black: linker (HY-76667)).
Nur für Forschungszwecke. Wir verkaufen nicht an Patienten.
- Reinheit : 99.3%
- CAS. Nr.: 2933135-82-9
- Formel: C36H40ClN9O5S
- Molecular Weight:746.28
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Speicherung:Powder -20°C, 3 years ; In solvent -80°C, 6 months , -20°C, 1 month
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Biologische Aktivität
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Chemical Information
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Biologische Aktivität
Beschreibung
IC50 & Target
[1]|
Lck 0.00838 pM (DC50) |
Cellular Effect
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Cell Line
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Type | Value | Description | References |
|---|---|---|---|---|
| KOPTK1 | LC50 |
0.083 pM
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Cytotoxicity (growth inhibition) against human KOPT-K1 T-ALL cells assessed via CellTiter-Glo (CTG) assay.
Cytotoxicity (growth inhibition) against human KOPT-K1 T-ALL cells assessed via CellTiter-Glo (CTG) assay.
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40672235 |
| CD34+ cells | LC50 |
726.42 nM
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Cytotoxicity against normal human cord blood CD34+ cells assessed via CellTiter-Glo (CTG) assay after 3 days incubation.
Cytotoxicity against normal human cord blood CD34+ cells assessed via CellTiter-Glo (CTG) assay after 3 days incubation.
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40672235 |
| PBMC | LC50 |
13.84 nM
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Cytotoxicity against normal human peripheral blood mononuclear cells (PBMCs) assessed via CellTiter-Glo (CTG) assay after 3 days incubation.
Cytotoxicity against normal human peripheral blood mononuclear cells (PBMCs) assessed via CellTiter-Glo (CTG) assay after 3 days incubation.
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40672235 |
| SUP-B15 | LC50 |
0.0123 pM
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Cytotoxicity against human SUP-B15 B-ALL cells (BCR-ABL fusion-positive) assessed via CellTiter-Glo (CTG) assay.
Cytotoxicity against human SUP-B15 B-ALL cells (BCR-ABL fusion-positive) assessed via CellTiter-Glo (CTG) assay.
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40672235 |
In Vitro
SJ11646 (10-7-100 nM; 1-24 h) induces CRBN-dependent LCK degradation and cytotoxicity in KOPT-K1 T-ALL cells with a DC50 of 0.00838 pM, and sustains growth inhibition and suppression of the LCK signaling pathway even after removal[1].
SJ11646 (10-2-104 nM; 96 h) exhibits selective cytotoxicity against LCK-dependent T-ALL blasts in xenografts, while showing no effect on LCK-independent T-ALL cells[1].
SJ11646 (100 nM; 24 h) selectively degrades SRC family kinases (including LCK) in KOPT-K1 T-ALL cells[1].
SJ11646 induces cereblon-dependent LCK degradation and cytotoxicity in KOPT-K1 T-ALL cells[1].
SJ11646 (10-3-10 μM; 72 h) exhibits cytotoxic activity against wild-type KOPT-K1 T-ALL cells[2].
SJ11646 (10-3-10 μM; 72 h) exhibits significantly reduced cytotoxic activity against Dasatinib (HY-10181)-resistant KOPT-K1 T-ALL cells harboring the LCKT316I mutation[2].
SJ11646 (10 nM; 24 h) induces significant LCK degradation in wild-type KOPT-K1 T-ALL cells, but this degradation effect is greatly attenuated in LCKT316I mutation-harboring drug-resistant KOPT-K1 cells at concentrations ranging from 10-3 to 10 μM[1].
SJ11646 (10-3-10 μM; 24 h) potently induces dose-dependent degradation of LCK in KOPT-K1 T-ALL cells[2].
SJ11646 (10-5-105 nM; 72 h) degrades BCR-ABL and induces potent cytotoxicity in SUP-B15 B-ALL cells, with an LC50 of 0.0123 pM[2].
SJ11646 (10-4-10 μM; 1 h) potently induces the formation of a ternary complex between LCKG415N and CRBN-DDB1[2].
SJ11646 (10-4-10 μM; 1 h) induces the formation of a ternary complex between wild-type LCK and CRBN-DDB1[2].
SJ11646 (10-2-104 nM; 72 h) exhibits lower cytotoxicity than Dasatinib against normal human umbilical cord blood CD34+ cells and peripheral blood mononuclear cells, and exerts comparable effects on resting and activated normal T cells[1].
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:KOPT-K1 T-ALL cells
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Concentration:10-7, 10-6, 10-5, 10-4, 10-3, 10-2, 10-1, 1, 10, 100 nM
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Incubation Time:24 h
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Result:Suppressed KOPT-K1 cell growth for up to 24 hours post-removal, with pLCK remaining undetectable for the same period.
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Cell Line:KOPT-K1 T-ALL cells, SUP-B15 B-ALL cells (BCR-ABL fusion-positive)
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Concentration:100 nM
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Incubation Time:6 h
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Result:Identified only CSK, LCK, and SRC as proteins uniquely affected by treatment, with DUSP6 and CISH (LCK downstream signaling proteins).
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Cell Line:Wildtype KOPT-K1 T-cell acute lymphoblastic leukemia (T-ALL) cells
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Concentration:10-3, 10-2, 10-1, 1, 10 μM
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Incubation Time:72 h
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Result:Exhibited cytotoxic activity against wildtype KOPT-K1 cells.
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Cell Line:Wildtype and dasatinib-resistant (LCK T316I) KOPT-K1 T-ALL cells
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Concentration:10 nM
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Incubation Time:24 h
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Result:Induced substantial LCK degradation in wildtype KOPT-K1 cells, but LCK degradation was greatly compromised in Dasatinib-resistant KOPT-K1 cells harboring the LCK T316I mutation.
Parmacokinetics
| Species | Dose | Route | T1/2 | AUC0-∞ |
|---|---|---|---|---|
| Mice[2] | 15 mg/kg | i.p. | 1.3 h | 1382 ng/mL·h |
In Vivo
SJ11646 (15 mg/kg; i.p.; single administration) extends the duration of > 50% LCK phosphorylation inhibition by 630% (up to 52 h) in T-ALL PDX mice, with a maximum pLCK depletion rate of 97%[2].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) (female, 8-12 weeks of age, tail vein injection of 2 million primary human T-ALL cells)[2]
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Dosage:15 mg/kg
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Administration:i.p.; once daily for 8 weeks
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Result:Reduced blood blast percentage to 12.9% and 0.9% in PDX_1 and PDX_2, respectively.
Markedly increased leukemia-free survival.
Caused no significant bodyweight changes or gross toxicities during treatment.
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Animal Model:NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) (female, 8-12 weeks of age, tail vein injection of primary human T-ALL cells)[2]
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Dosage:15 mg/kg
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Administration:i.p.; single dose
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Result:Induced rapid and complete loss of pLCK within 3 hours post-injection, with prolonged suppression of pLCK lasting at least 24 hours and concomitant LCK degradation.
Chemical Information
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CAS. Nr. 2933135-82-9
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Appearance Solid
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Molecular Weight 746.28
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Formel C36H40ClN9O5S
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Color White to off-white
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SMILES
O=C(C1=CN=C(NC2=NC(C)=NC(N3CCN(CCCNC(COC4=CC=C(C(CC5)C(NC5=O)=O)C=C4)=O)CC3)=C2)S1)NC6=C(C)C=CC=C6Cl
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Versand
Room temperature in continental US; may vary elsewhere.
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Speicherung
Powder -20°C 3 years In solvent -80°C 6 months -20°C 1 month
Protokoll
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Cell Cytotoxicity Assay
Cytotoxicity assays are usually based on the assessment of cell membrane damage, which can also be indirectly detected by measuring cell viability. Detection methods include MTT assay, CKK-8 assay, LDH assay and ATP assay, etc.
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Mammalian live/dead viability and cytotoxicity staining
Live/dead viability and cytotoxicity staining assays are based on the simultaneous detection of intracellular esterase activity in metabolically active (viable) cells and membrane integrity loss in non-viable cells. In commonly used dual-staining approaches, membrane-permeant fluorogenic substrates are converted by intracellular esterases into fluorescent products in live cells, while impermeant DNA-binding dyes selectively enter cells with compromised plasma membranes and label nucleic acids in dead or dying cells, enabling discrimination between viable and non-viable populations by fluorescence microscopy or flow cytometry.
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Genotoxicity/Mutagenicity Study
The bacterial reverse mutation assay detects point mutations that restore amino-acid prototrophy in auxotrophic Salmonella typhimurium or Escherichia coli tester strains; after exposure to a test article, mutagenic activity is read out as an increased number of revertant colonies on minimal agar compared with the vehicle control. The assay uses tester strains with different mutation targets so that base-substitution and frameshift mutagens can be detected, and testing is performed with and without exogenous mammalian metabolic activation because some chemicals require biotransformation to become mutagenic.
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Cell Viability Determination by MTT Colorimetric Assay
The following protocol uses the MTT colorimetric assay as a classic literature-established method for assessing cell viability/metabolic activity in cultured mammalian cells. MTT[3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] is reduced by metabolically active cells to a colored formazan product; the amount of formazan is quantified spectrophotometrically and provides an indirect measure of metabolically active viable cells. Importantly, MTT reduction reflects cellular oxidoreductase/metabolic activity rather than an absolute direct count of living cells, so changes in cellular metabolism can alter the signal independently of cell number.
Reinheit & Dokumentation
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Data Sheet (280 KB)
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SDS (252 KB)
- English - EN (252 KB)
- Français - FR (252 KB)
- Deutsch - DE (252 KB)
- Norwegian - NO (252 KB)
- Español - ES (252 KB)
- Swedish - SV (252 KB)
- Italian - IT (252 KB)
- Korean - KR (252 KB)
- Portuguese - PT (252 KB)
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Handling Instructions (2659 KB)
Verweise
[1]. Yang JJ, et al. LCK-targeting molecular glues overcome resistance to inhibitor-based therapy in T-cell acute lymphoblastic leukemia. bioRxiv [Preprint]. 2025 Jul 7:2025.07.03.663042. [Content Brief]
[2]. Hu J, et al. Preclinical evaluation of proteolytic targeting of LCK as a therapeutic approach in T cell acute lymphoblastic leukemia. Science translational medicine. 2022 Aug 24;14(659):eabo5228. [Content Brief]
Calculators
Konzentration (Stammlösung) × Volumen (Stammlösung) = Konzentration (Ziellösung) × Volumen (Ziellösung)
SJ11646 Related Classifications
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