AZD4956
AZD4956 is a potent and selective DNA polymerase theta (POLQ) inhibitor. AZD4956 exhibits an IC50 value of less than 3 μmol/L against POLQ and 3.4 μmol/L against MMEJ. AZD4956 suppresses the MMEJ pathway and enhances the activity of DNA-damaging agents in HRR-deficient cellular contexts. AZD4956 shows antitumor activity in BRCA1/2-mutated triple-negative breast cancer and prostate cancer models. AZD4956 can be used for the study of homologous recombination-deficient tumors.
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- CAS No.: 3045469-78-8
- Formule: C28H25Cl2N5O4
- Masse moléculaire:566.44
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Please store the product under the recommended conditions in the Certificate of Analysis.
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Activité biologique
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Activité biologique
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Human pol θ |
AZD4956 potently inhibits purified DNA polymerase theta (POLQ) in a biochemical assay with an IC50 of < 3 nmol/L[1].
AZD4956 inhibits microhomology-mediated end joining (MMEJ) in HEK-293T cells with an IC50 of 3.4 nmol/L, phenocopying genetic POLQ deletion[1].
AZD4956 exhibits significant synergistic combination effects with DNA-damaging agents such as Saruparib (HY-132167), preferentially in HRR-deficient cancer cells, whereas no significant synergy is observed with the non-DNA-damaging agent MMAE[1].
AZD4956 (200 nM; 48 h), combined with Saruparib, significantly increases DNA damage markers (KAP1 phosphorylation, 53BP1 foci) and chromosomal aberrations in DLD-1 BRCA2+ cells[1].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
AZD4956 (100 mg/kg; BID) combined with Saruparib (HY-132167) (1 mg/kg; QD) achieves significant antitumor activity with TGI values of 110% in BRCA2-mutated mHSPC PDX model (C-901) and 101% in BRCA1-mutated TNBC PDX model (HBCx28) in vivo[1].
AZD4956 (100 mg/kg; BID) combined with Saruparib (HY-132167) (1 mg/kg; QD) delays the acquisition of resistance in BRCA1-mutated TNBC PDX model (PDX179)[1].
AZD4956 (3-50 mg/kg; BID) combined with Saruparib (HY-132167) (1 mg/kg; QD) exhibits dose-dependent enhanced antitumor activity in BRCA1-mutated TNBC PDX model (PDX127)[1].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:Female immunocompromised mice bearing PDX127 (BRCA1m TNBC) PDX tumors were treated with AZD4956 at multiple doses in combination with saruparib.[1]
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Dosage:AZD4956 3/10/25/50 mg/kg + saruparib 1 mg/kg
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Administration:AZD4956 twice daily (BID), saruparib once daily (QD); throughout the treatment period
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Result:Exhibited dose-dependent enhanced antitumor activity, with higher AZD4956 doses producing greater tumor growth inhibition and prolonged durable responses compared to saruparib monotherapy.
Increased micro-nucleated red blood cells in peripheral blood, indicating on-target activity of POLQ inhibition.
Chemical Information
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CAS No. 3045469-78-8
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Masse moléculaire 566.44
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Formule C28H25Cl2N5O4
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SMILES
ClC1=CC=C(C#N)C(CN2C3=NC=NC(OC4(C)CC4)=C3N=C2C5=CC=CC(OCC[C@@H](C)C(O)=O)=C5Cl)=C1
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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)
AZD4956 Related Classifications
HY-183630 Related Classifications
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- AZD4956
- 3045469-78-8
- AZD 4956
- AZD-4956
- DNA/RNA Synthesis
- DNA polymerase theta
- HRR-deficient cancers
- HEK-293T cells
- patient-derived xenograft models
- PARP inhibitors
- DLD-1 BRCA2+ cells
- POLQ
- BRCA1-mutant triple-negative breast cancer
- DNA double-strand break repair pathway
- microhomology-mediated end joining
- Inhibitor
- inhibitor
- inhibit