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].
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 (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 (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 (1 mg/kg; QD) exhibits dose-dependent enhanced antitumor activity in BRCA1-mutated TNBC PDX model (PDX127)[1].
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, 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].
References:
[1]. Forment JV, et al. AZD4956, a potent and selective inhibitor of DNA polymerase theta, enhances the activity of DNA-damaging agents in HRR defective cellular backgrounds and improves efficacy of the new generation PARP1-selective inhibitor, saruparib. Cancer Res. 2026;86(7 Suppl):Abstract 230.
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 (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 (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 (1 mg/kg; QD) exhibits dose-dependent enhanced antitumor activity in BRCA1-mutated TNBC PDX model (PDX127)[1].
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, 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].
References:
[1]. Forment JV, et al. AZD4956, a potent and selective inhibitor of DNA polymerase theta, enhances the activity of DNA-damaging agents in HRR defective cellular backgrounds and improves efficacy of the new generation PARP1-selective inhibitor, saruparib. Cancer Res. 2026;86(7 Suppl):Abstract 230.