AZD9750 is an orally active, Cereblon (CRBN)-recruiting, androgen receptor (AR)-targeted PROTAC degrader. AZD9750 induces the proteasome-dependent degradation of both wild-type AR and the drug-resistant mutant ARL702H, thereby inhibiting the AR signaling pathway. AZD9750 suppresses tumor growth in mouse prostate cancer xenograft models and has been utilized in prostate cancer research[1]. (Pink: Adenosine Receptor ligand; Blue: Cereblon ligand; Black: linker).
In Vitro, AZD9750 (compound 3n) (0.010-0.012 μM; 24 h) potently degrades wild-type ARWT (with a DC50 of 0.010 μM) in LNCaP cells, as well as mutant ARL702H (with a DC50 of 0.012 μM) in LNCaPL702H cells, after 24 h of treatment.
AZD9750 (0.01-1 μM; 24 h) dose-dependently inhibits the expression of AR-regulated genes (PSA and TMPRSS2) in LNCaP cells[1].
AZD9750 (0.001-1 μM; 10 d) inhibits the proliferation of LNCaP cells in a dose-dependent manner, with the strongest effect observed at the concentration of 1 μM[1].
AZD9750 shows no mitochondrial toxicity in HepG2 cells, with an IC50 as high as 85 μM under galactose conditions and no significant cytotoxicity[1].
AZD9750 (1 μM; 24 h) does not induce the degradation of Ikaros or Aiolos in NB4 cells[1].
In Vivo, AZD9750 (3-60 mg/kg; p.o.; daily; 10 days) dose-dependently reduces seminal vesicle weight in male SCID mice[1].
AZD9750 (30 mg/kg; p.o.; daily; 25 days) achieves 85% tumor growth inhibition and an 86% reduction in AR protein levels in the ST1273 prostate cancer PDX model[1].
References:
[1]. Scott JS, et al. Discovery of AZD9750, an Orally Bioavailable Androgen Receptor Degrader for the Treatment of Prostate Cancer. J Med Chem. 2026;69(3):3209-3232.