GPX4-AUTAC
GPX4-AUTAC is a GPX4-targeting autophagy-mediated degrader (AUTAC). GPX4-AUTAC consists of an inhibitor ML162-yne (HY-153748), a degradation tag FBnG (HY-W073762) and a glycol linker (HY-W021401). GPX4-AUTAC promotes the ubiquitination of GPX4 by E3 ligase TRAF6, and enhances the binding with GPX4 and p62, leading to the selective autophagy-dependent degradation of GPX4. GPX4-AUTAC significantly induces ferroptosis and shows a potent anti-cancer activity in breast cancer cells, breast cancer-derived organoids (PDOs) and MDA-MB-231 tumor xenograft mice model, with potent synergistic effects when combined with Sulfasalazine (SAS) (HY-14655) or chemotherapy drugs (Paclitaxel (HY-B0015) or Cisplatin (HY-17394)).
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- CAS No.: 3060458-90-1
- 화학식: C50H55Cl2FN12O9S2
- 분자량:1122.08
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보관:
Please store the product under the recommended conditions in the Certificate of Analysis.
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Biological Activity
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Chemical Information
- Protocol
- 순도&문서
- References
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Help & FAQs
Biological Activity
제품 설명
IC50 & Target
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GPX4 |
In Vitro
GPX4-AUTAC (5-80 μM, 12-72 h) significantly reduces the protein level of GPX4 in a dose- and time-dependent manner, but barely affects the mRNA level of GPX4 in MDA-MB-231 and MCF-7 cells [1].
GPX4-AUTAC (20-40 μM, 24 h) effectively reduces the protein level of GPX4 in ovarian cancer, lung cancer, melanoma, and glioma cells[1].
GPX4-AUTAC (10 μM, 24-96 h, 37-57°C) continuously down-regulates GPX4 protein level for 96 h and significantly enhances the thermal stability of GPX4 in heat-denatured intact cells and cell lysates in MDA-MB-231 and MCF-7 cells[1].
GPX4-AUTAC (5-80 μM, 24 h) selectively degrades GPX4 without influence other selenoproteins expression, such as of GPX1, TXNRD1 (GPX4 homologs) or HK2 (a TRAF6/p62 substrate)[1].
GPX4-AUTAC selectively degrades GPX4 and induces ferroptosis in tumor cells (MDA-MB-231 cells) with minimal effect on normal cells (MCF-10A cells)[1].
GPX4-AUTAC (10 μM, 24 h) autophagy-dependently accelerates GPX4 degradation, increases polyubiquitylation of GPX4, specifically the endogenous and exogenous K63-linked ubiquitin chains in HEK293T cells[1].
GPX4-AUTAC (10-40 μM, 12 h) is reversed by PYR-41, NH4Cl and 3-MA to reduce the down-regulation of GPX4 in MDA-MB-231 cells[1].
GPX4-AUTAC (24 h) induces co-localization of GPX4 and p62 and increases co-localization of GPX4 with LC3B or LAMP2 in PDOs[1].
GPX4-AUTAC (40?μM, 24?h) selectively targets GPX4 and ferroptosis is significantly enriched in MDA-MB-231 cells[1].
GPX4-AUTAC (5-40 μM, 72 h) has a specific ferroptosis inductive effect, and significantly enhanced the lipid ROS and promoted accumulation of Fe2+ in MDA-MB-231 cells, but only fully rescued by the ferroptosis inhibitor Ferrostatin-1 (Fer-1) (HY-100579) in MCF-7 cells[1].
GPX4-AUTAC (5-80 μM) induces ferroptosis with mitochondrial dysfunction (abnormal morphology, dense content and disrupted crista) and significant increase in mRNA levels of PTGS2 in MDA-MB-231[1].
GPX4-AUTAC (5-40 μM, 24-96 h) dose- and time-dependently inhibited cell viability and proliferation, with insensitivity to knock-down of GPX4 in both MDA-MB-231 and MCF-7 cells[1].
GPX4-AUTAC (5-40 μM, 4 days) significantly inhibits the growth of PDOs with reducing diameter and bright-field, and PDOs with high expression of GPX4 increases sensitivity [1].
GPX4-AUTAC (10-20 μM, 4 days) down-regulates GPX4 expression and induces ferroptosis with high level of 4-HNE, and inhibits cancer cell proliferation in PDOs with low level of Ki67[1].
GPX4-AUTAC induces much more ferroptosis and has a stronger anti-cancer effect in combination with Sulfasalazine compared to Sulfasalazine alone treatment in MDA-MB-231 and MCF-7 cells and PDOs [1].
GPX4-AUTAC (10?μM, 72 h or 4 days) sensitizes MDA-MB-231 and HCC1806 cells to chemotherapy and synergistically inhibits cell viability and proliferation and the growth of PDOs in combination with chemotherapy drugs (Paclitaxel or Cisplatin)[1].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Cell Line:MCF-7 cells
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Concentration:5, 10, 20, 40 μM
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Incubation Time:72 h after Fer-1, Z-VAD-FMK, Nec-1, Olaparib or VX765 1 h
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Result:Had a specific ferroptosis inductive effect , only fully rescued by the ferroptosis inhibitor ferrostatin-1 (Fer-1), but not by the inhibitor of apoptosis (Z-VAD-FMK), necroptosis (Nec-1), parthanatos (Olaparib), or pyroptosis (VX765) in MCF-7 cells.
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Cell Line:MDA-MB-231 cells, MCF-7 cells
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Concentration:MDA-MB-231 cells, MCF-7 cells (5, 10, 20, 40 μM), shNT, shGPX4 cells (10, 20, 40, 80 μM)
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Incubation Time:72 h
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Result:Dose-dependently inhibited tumor cell viability in both MDA-MB-231, MCF-7 and shGPX4 cells.
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Cell Line:MDA-MB-231 cells, MCF-7 cells
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Concentration:5, 10 μM
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Incubation Time:24, 48, 72, 96 h
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Result:Dose- and time-dependently inhibited tumor cell proliferation in both MDA-MB-231 and MCF-7 cells.
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Cell Line:MDA-MB-231 cells, MCF-7 cells, MCF-10A cells
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Concentration:MDA-MB-231 cells, MCF-7 cells, MCF-10A cells (5, 10, 20, 40, 80 μM)
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Incubation Time:12, 24, 48, 72 h
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Result:Significantly reduced the expression of GPX4 protein in a dose- and time-dependent manner.
Significantly reduced the expression of GPX4 in MDA-MB-231 cells with minimal effect on MCF-10A cells at 24 h.
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Cell Line:MDA-MB-231 cells, MCF-7 cells
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Concentration:10 μM
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Incubation Time:24, 48, 72, 96 h
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Result:Continuously down-regulated GPX4 protein level for 96 h after wash-out in MDA-MB-231 and MCF-7 cells.
Significantly enhanced the thermal stability of GPX4 in heat-denatured intact cells and cell lysates in MDA-MB-231 and MCF-7 cells at 37-57℃ and 24 h.
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Cell Line:MDA-MB-231 cells, HEK293T cells
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Concentration:10, 40 μM
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Incubation Time:12 h
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Result:Significantly accelerated the turnover rate of GPX4 in MDA-MB-231 cells when added CHX at 10 μM.
Down-regulated GPX4 expression, but this effect reversed by PYR-41 (an inhibitor of cell-permeable ubiquitin E1 enzyme) in MDA-MB-231 cells at 10 μM.
Enhanced the down-regulation of GPX4 promoted by overexpression of p62, but rescued by knockdown of p62 in HEK293T cells at 40 μM.
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Cell Line:MDA-MB-231 cells, MCF-7 cells
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Concentration:5, 10, 20, 40, 80 μM
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Incubation Time:24 h
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Result:Played a regulatory role at the post-translational level ,and barely affected the mRNA level of GPX4 in both MDA-MB-231 and MCF-7 cells.
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Cell Line:MDA-MB-231 cells
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Concentration:5, 10, 20, 40 μM
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Incubation Time:72 h
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Result:Significantly enhanced the lipid ROS and promoted accumulation of Fe<>sup2+ in MDA-MB-231 cells.
In Vivo
GPX4-AUTAC (10-20mg/kg combined Sulfasalazine 100?mg/kg, i.p., daily for 10-12 days) synergizes with Sulfasalazine to exert strong tumor suppressive activity via inducing ferroptosis with no measurable toxicity in MDA-MB-231 tumor xenograft mice model[1].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:Female BALB/c nude mice (4-6 weeks old) were injected subcutaneously into the right flank with MDA-MB-231 cells (5 × 106 cells/mouse) [1].
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Dosage:10, 20mg/kg
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Administration:i.p., daily for 10-12 days when the tumor size reached 50-100 mm
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Result:Selectively degraded GPX4 in tumors tissues, but not in the normal tissues including the heart, lung, liver, spleen, and kidney.
Significantly decreased tumor weights and volumes in MDA-MB-231 tumor xenograft mice model.
Markedly decreased the protein level of GPX4 in MDA-MB-231 tumor xenograft mice model.
Effectively decreased percentage of Ki67, but increased percentage of Ki67 4-HNE in MDA-MB-231 tumor xenograft mice model.
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Animal Model:Female BALB/c nude mice (4-6 weeks old) were injected subcutaneously into the right flank with MDA-MB-231 cells (5 × 106 cells/mouse) [1].
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Dosage:10, 20mg/kg or Sulfasalazine 100 mg/kg
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Administration:i.p., daily for 10-12 days when the tumor size reached 50-100 mm
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Result:Had a synergistic inhibitory effect on tumor growth combined with SAS in MDA-MB-231 tumor xenograft mice model.
Significantly decreased expressions of GPX4 and Ki67 and increased expression of 4-HNE combined with SAS in MDA-MB-231 tumor xenograft mice model.
- Autophagy
- Patient-Derived Xenograft (PDX)
- Splenic/Portal-Vein Liver Metastasis Xenograft
- Ferroptosis Solutions
- Lysosome and acidic-vesicle live-cell staining
- Subcutaneous Cell-Line-Derived Xenograft
- Macroautophagy Solutions
- Breast Cancer Modeling
- Orthotopic Cell-Line Xenograft
- Intraperitoneal/Peritoneal Dissemination Xenograft
Chemical Information
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CAS No. 3060458-90-1
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분자량 1122.08
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화학식 C50H55Cl2FN12O9S2
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SMILES
O=C(C(N(C1=CC(Cl)=C(OCC(N=N2)=CN2CCOCCOCCOCCNC([C@H](CSC3=NC4=C(N3CC5=CC=C(C=C5)F)N=C(NC4=O)N)NC(C)=O)=O)C=C1)C(CCl)=O)C6=CC=CS6)NCCC7=CC=CC=C7
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선적
Room temperature in continental US; may vary elsewhere.
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보관
Please store the product under the recommended conditions in the Certificate of Analysis.
순도&문서
References
Calculators
Concentration (start) × Volume (start) = Concentration (final) × Volume (final)
GPX4-AUTAC Related Classifications
HY-176220 Related Classifications
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