2. Cell Cycle/DNA Damage
  3. DNA/RNA Synthesis
  4. 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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AZD4956

AZD4956 Chemical Structure

CAS No. : 3045469-78-8

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Description

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[1].

IC50 & Target[1]

Human pol θ

 

In Vitro

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 Related Antibodies
In Vivo

AZD4956 (100 mg/kg; BID) shows modest monotherapy antitumor activity in BRCA2-mutated TNBC PDX model (ST4316B) and PALB2-mutated TNBC PDX model (T298) in vivo[1].
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.

Animal Model: Female immunocompromised mice bearing PDX127 (BRCA1m TNBC) PDX tumors were treated with AZD4956 at multiple doses in combination with saruparib.[1]
Dosage: AZD4956 3/10/25/50 mg/kg + saruparib 1 mg/kg
Administration: AZD4956 twice daily (BID), saruparib once daily (QD); throughout the treatment period
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.
Molecular Weight

566.44

Formula

C28H25Cl2N5O4
CAS No.
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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Room temperature in continental US; may vary elsewhere.
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References
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AZD4956 Related Classifications

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Help & FAQs
  • 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:

AZD49563045469-78-8AZD 4956AZD-4956DNA/RNA SynthesisDNA polymerase thetaHRR-deficient cancersHEK-293T cellspatient-derived xenograft modelsPARP inhibitorsDLD-1 BRCA2+ cellsPOLQBRCA1-mutant triple-negative breast cancerDNA double-strand break repair pathwaymicrohomology-mediated end joiningInhibitorinhibitorinhibit

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