AZD5335
AZD5335 is an ADC targeting FRα, with an IC50 of 10.6 nM against human FRα. AZD5335 specifically binds to FRα, mediates internalization and trafficking to lysosomal compartments, while delivering a topoisomerase I inhibitor payload that traps TOP1-DNA cleavage complexes. AZD5335 induces DNA damage response via the ATR, ATM, Chk1 and Chk2 signaling pathways, and increases the levels of phosphorylated KAP1, phosphorylated RPA, phosphorylated γH2AX, as well as PARP cleavage. AZD5335 exhibits bystander cytotoxicity against FRα-negative cells co-cultured with FRα-expressing cells. AZD5335 induces potent and durable responses and complete regression in ovarian cancer models, including models with low FRα expression and models resistant to Elahere, with enhanced efficacy when combined with Carboplatin, Bevacizumab or poly (ADP-ribose) polymerase inhibitors. AZD5335 can be used for ovarian cancer research.
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研究用途以外に使用した場合、当社は一切の責任を負いかねます。
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保管条件:
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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生物活性
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化学情報
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Help & FAQs
生物活性
製品説明
IC50 & Target
[1]|
FR-α 10.6 nM (IC50) |
Chk1 |
Chk2 |
Cellular Effect
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Cell Line
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Type | Value | Description | References |
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| KB | IC50 |
0.5270 nM
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Cytotoxicity against FRα-expressing KB cancer cells assessed as reduction in cell viability incubated for 6 days by CellTiter-Glo (CTG) 2.0 assay.
Cytotoxicity against FRα-expressing KB cancer cells assessed as reduction in cell viability incubated for 6 days by CellTiter-Glo (CTG) 2.0 assay.
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41091103 |
| JEG-3 | IC50 |
2.091 nM
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Cytotoxicity against FRα-expressing Jeg-3 cancer cells assessed as reduction in cell viability incubated for 6 days by CellTiter-Glo (CTG) 2.0 assay.
Cytotoxicity against FRα-expressing Jeg-3 cancer cells assessed as reduction in cell viability incubated for 6 days by CellTiter-Glo (CTG) 2.0 assay.
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41091103 |
| IGROV-1 | IC50 |
5.284 nM
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Cytotoxicity against FRα-expressing IGROV-1 cancer cells assessed as reduction in cell viability incubated for 6 days by CellTiter-Glo (CTG) 2.0 assay.
Cytotoxicity against FRα-expressing IGROV-1 cancer cells assessed as reduction in cell viability incubated for 6 days by CellTiter-Glo (CTG) 2.0 assay.
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41091103 |
体外実験
AZD5335 (0.001707-666.66 nM; 6 days) potently reduces the viability of FRα-expressing KB, Jeg-3 and IGROV-1 cancer cells in vitro, with IC50 values of 0.5270 nM, 2.091 nM and 5.284 nM, respectively[1].
AZD5335 (0-300 nM; 6 days) exhibits bystander cytotoxicity and reduces the survival rate of FRα-negative lucKB_FRα-KO cells when co-cultured with FRα-expressing KB cells[1].
AZD5335 (0.104-30 µg/mL; 6 days) exhibits synergistic cytotoxic activity with Carboplatin (HY-17393) and Saruparib (HY-132167) in FRα-expressing KB, Jeg-3 and IGROV-1 cancer cells[1].
AZD5335 (66.7 nM; 24-72 h) activates the DNA damage response pathway in FRα-expressing KB cancer cells, which is consistent with the mechanism of action of its TOP1i payload[1].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Cell Line:FRα-expressing KB, Jeg-3, and IGROV-1 cancer cell lines
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Concentration:0.001707-666.66 nM
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Incubation Time:6 days
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Result:Reduced cell viability in all three FRα-expressing cell lines.
Inhibited KB cell viability with an IC50 of 0.5270 nM.
Inhibited Jeg-3 cell viability with an IC50 of 2.091 nM.
Inhibited IGROV-1 cell viability with an IC50 of 5.284 nM.
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Cell Line:FRα-expressing KB, Jeg-3, and IGROV-1 cancer cell lines
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Concentration:0.104-30 µg/mL
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Incubation Time:6 days
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Result:Enhanced cytotoxicity across all three cell lines when combined with Carboplatin compared to monotherapy, with HSA synergy scores of 30.24 (Jeg-3), 4.218 (KB), and 2.339 (IGROV-1).
Yielded minimal to no added benefit when combined with Bevacizumab, with low HSA synergy scores.\nEnhanced cytotoxicity across all three cell lines when combined with saruparib compared to either single agent alone, with HSA synergy scores of 40.76 (Jeg-3), 23.81 (KB), and 7.348 (IGROV-1).
体内実験
AZD5335 (1.25-5 mg/kg; intravenous injection; single administration) induces 53.37% tumor growth inhibition in FRα-low expressing SKOV-3 ovarian cancer xenografts at a single intravenous dose of 5 mg/kg[1].
AZD5335 (2.5-5 mg/kg; intravenous injection; single dose) induces an overall response rate of 82% at a single intravenous dose of 2.5 mg/kg and 76% at a single intravenous dose of 5 mg/kg in a panel of ovarian cancer patient-derived xenograft models with varying FRα expression levels[1].
AZD5335 (2.5-5 mg/kg; intravenous injection; single administration) induces significant and persistent tumor growth inhibition in Elahere-intolerant ovarian cancer xenograft models[1].
AZD5335 (intravenous injection; single dose, 2.5 mg/kg) induces 85.96% tumor growth inhibition in FRα-low-expressing OV90 ovarian cancer xenograft models; its efficacy is enhanced when combined with Bevacizumab (HY-P9906), Carboplatin, or both, with a maximum TGI of up to 98.66%[1].
AZD5335 (1.25-2.5 mg/kg, intravenous injection, single dose; or in combination with a 1 mg/kg poly (ADP-ribose) polymerase inhibitor administered orally daily for 28 days) enhances tumor growth inhibition when combined with the poly (ADP-ribose) polymerase inhibitor in low/very low FRα ovarian cancer 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:CB-17 SCID (female, ovarian cancer KB cell-derived subcutaneous xenografts)[1]
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Dosage:1.25 mg/kg; 2.5 mg/kg; 5 mg/kg
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Administration:i.v.; single dose
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Result:Induced complete and durable tumor regression with 100% tumor growth inhibition (TGI) at 5 mg/kg.
Resulted in 55.17% TGI at 2.5 mg/kg.
Resulted in 78.38% TGI at 1.25 mg/kg.
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Animal Model:CB-17 SCID (female, ovarian cancer IGROV-1 cell-derived subcutaneous xenografts)[1]
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Dosage:1.25 mg/kg; 2.5 mg/kg; 5 mg/kg
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Administration:i.v.; single dose
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Result:Resulted in 95.55% TGI at 5 mg/kg.
Resulted in 86.75% TGI at 2.5 mg/kg.
Resulted in 43.8% TGI at 1.25 mg/kg.
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Animal Model:NOD/SCID gamma (NSG) (female, ovarian cancer OVCAR-3 cell-derived subcutaneous xenografts)[1]
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Dosage:1.25 mg/kg; 2.5 mg/kg; 5 mg/kg
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Administration:i.v.; single dose
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Result:Resulted in greater than 80% TGI across all tested doses.
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Animal Model:NOD/SCID gamma (NSG) (female, ovarian cancer SKOV-3 cell-derived subcutaneous xenografts)[1]
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Dosage:1.25 mg/kg; 2.5 mg/kg; 5 mg/kg
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Administration:i.v.; single dose
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Result:Resulted in 53.37% TGI.
Induced dose-dependent reductions in TGI at lower doses, with only the 5 mg/kg dose showing significant activity.
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Animal Model:NOD/SCID gamma (NSG) (female, ovarian cancer patient-derived subcutaneous xenografts with variable FRα expression)[1]
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Dosage:2.5 mg/kg; 5 mg/kg
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Administration:i.v.; single dose
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Result:Resulted in an 82% overall response rate, with 14 of 17 models exhibiting a tumor volume reduction of 30% or greater, including 4 of 4 FRα-high models, 10 of 11 FRα-low models, and 0 of 2 FRα-ultra-low models.
Resulted in a 76% overall response rate, with 13 of 17 models exhibiting a tumor volume reduction of 30% or greater, including 4 of 4 FRα-high models, 9 of 11 FRα-low models, and 0 of 2 FRα-ultra-low models, with deeper, dose-dependent responses observed compared to the 2.5 mg/kg dose.
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Animal Model:NOD/SCID gamma (NSG) (female, Elahere-ineligible ovarian cancer xenografts: CTG-3226 PDX, OV0857-CIS PDX, OVCAR-3 CDX)[1]
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Dosage:2.5 mg/kg; 5 mg/kg
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Administration:i.v.; single dose
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Result:Demonstrated significant tumor growth inhibition associated with durable responses in all three Elahere-ineligible models.
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Animal Model:NOD/SCID gamma (NSG) (female, ovarian cancer OV90 cell-derived subcutaneous xenografts, FRα-low)[1]
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Dosage:2.5 mg/kg (monotherapy; combination with Bevacizumab; combination with Carboplatin; combination with Bevacizumab and Carboplatin)
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Administration:i.v.; single dose; monotherapy or in combination with 5 mg/kg bevacizumab i.p. single dose, 100 mg/kg carboplatin i.p. single dose, or both
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Result:Resulted in 85.96% TGI as monotherapy.
Resulted in 98.66% TGI when combined with Bevacizumab.
Resulted in 96.38% TGI when combined with Carboplatin.
Resulted in 98.63% TGI when combined with Bevacizumab and carboplatin.
Showed enhanced efficacy with all combination treatments compared to monotherapy.
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Animal Model:NOD/SCID gamma (NSG) (female, ovarian cancer OVCAR-3 CDX, OV2022F PDX, CTG-3783 PDX, low/ultra-low FRα expression)[1]
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Dosage:1.25 mg/kg (OVCAR-3, OV2022F models; monotherapy or combination); 2.5 mg/kg (CTG-3783 model; monotherapy or combination)
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Administration:i.v.; single dose; monotherapy or in combination with 1 mg/kg poly(ADP-ribose) polymerase inhibitor p.o. daily for 28 days
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Result:Resulted in 86.14% TGI as monotherapy and 92.83% TGI in combination with poly(ADP-ribose) polymerase inhibitor in OVCAR-3.
Resulted in 53.91% TGI as monotherapy and 97.15% TGI in combination with poly(ADP-ribose) polymerase inhibitor in OV2022F.
Resulted in 72.82% TGI as monotherapy and 95.49% TGI in combination with poly(ADP-ribose) polymerase inhibitor in CTG-3783.
Showed enhanced efficacy with all combination treatments compared to monotherapy.
化学情報
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SMILES
[AZD5335]
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輸送条件
Room temperature in continental US; may vary elsewhere.
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保管条件
Please store the product under the recommended conditions in the Certificate of Analysis.
純度とドキュメンテーション
参考文献
Calculators
濃度 (開始) × 体積 (開始) = 濃度 (終了) × 体積 (終了)
AZD5335 関連分類
HY-188120 関連分類
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