2. Autophagy PROTAC Metabolic Enzyme/Protease Apoptosis
  3. AUTACs Autophagy Glutathione Peroxidase Ferroptosis
  4. 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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GPX4-AUTAC Chemical Structure

GPX4-AUTAC Chemical Structure

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GPX4-AUTAC Related Antibodies

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Description

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))[1].

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℃) 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.

GPX4-AUTAC Related Antibodies

Cell Viability Assay[1]

Cell Line: MCF-7 cells
Concentration: 5, 10, 20, 40 μM
Incubation Time: 72 h after Fer-1, Z-VAD-FMK, Nec-1, Olaparib or VX765 1 h
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.

Cell Viability Assay[1]

Cell Line: MDA-MB-231 cells, MCF-7 cells
Concentration: MDA-MB-231 cells, MCF-7 cells (5, 10, 20, 40 μM), shNT, shGPX4 cells (10, 20, 40, 80 μM)
Incubation Time: 72 h
Result: Dose-dependently inhibited tumor cell viability in both MDA-MB-231, MCF-7 and shGPX4 cells.

Cell Proliferation Assay[1]

Cell Line: MDA-MB-231 cells, MCF-7 cells
Concentration: 5, 10 μM
Incubation Time: 24, 48, 72, 96 h
Result: Dose- and time-dependently inhibited tumor cell proliferation in both MDA-MB-231 and MCF-7 cells.

Western Blot Analysis[1]

Cell Line: MDA-MB-231 cells, MCF-7 cells, MCF-10A cells
Concentration: MDA-MB-231 cells, MCF-7 cells, MCF-10A cells (5, 10, 20, 40, 80 μM)
Incubation Time: 12, 24, 48, 72 h
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.

Western Blot Analysis[1]

Cell Line: MDA-MB-231 cells, MCF-7 cells
Concentration: 10 μM
Incubation Time: 24, 48, 72, 96 h
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.

Western Blot Analysis[1]

Cell Line: MDA-MB-231 cells, HEK293T cells
Concentration: 10, 40 μM
Incubation Time: 12 h
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.

Real Time qPCR[1]

Cell Line: MDA-MB-231 cells, MCF-7 cells
Concentration: 5, 10, 20, 40, 80 μM
Incubation Time: 24 h
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.

Immunofluorescence[1]

Cell Line: MDA-MB-231 cells
Concentration: 5, 10, 20, 40 μM
Incubation Time: 72 h
Result: Significantly enhanced the lipid ROS and promoted accumulation of Fe<>sup2+ in MDA-MB-231 cells.
In Vivo

GPX4-AUTAC (10-20 mg/kg, i.p., daily for 10-12 days) has a potent anti-cancer activity, and significantly reduces tumor weights and volumes, GPX4 protein levels, and percentage of Ki67 while increasing 4-HNE levels with no significant toxicity in vital organs, through preferentially accumulation and selectively degradation of GPX4 in tumor tissues of MDA-MB-231 tumor xenograft mice model (minimal effect on normal tissues)[1].
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.

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].
Dosage: 10, 20mg/kg
Administration: i.p., daily for 10-12 days when the tumor size reached 50-100 mm
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.
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].
Dosage: 10, 20mg/kg or Sulfasalazine 100 mg/kg
Administration: i.p., daily for 10-12 days when the tumor size reached 50-100 mm
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.
Molecular Weight

1124.10

Formula

C50H57Cl2FN12O9S2
SMILES

O=C(C(N(C1=CC(Cl)=C(OCC(NN2)=CN2CCOCCOCCOCCNC(C(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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GPX4-AUTAC Related Classifications

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  • 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:

GPX4-AUTACAUTACsAutophagyGlutathione PeroxidaseFerroptosisAutophagy-targeting chimerasAUTACGPX4AnticancerPDOsMDA-MB-231 cellsMCF-7 cellsHEK293T cellstumor xenograft mice modelInhibitorinhibitorinhibit

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