AZD5305 is a highly selective PARP1 inhibitor that induces cancer cell death by precisely targeting PARP1 and disrupting the DNA damage repair mechanism in tumor cells. AZD5305 exhibits approximately 500-fold greater selectivity for PARP1 (IC₅₀=3nM) over PARP2 (IC₅₀=1400nM)[1-2]. AZD5305 is indicated for the treatment of solid tumors harboring mutations in homologous recombination repair (HRR) genes, including BRCA1, BRCA2, PALB2, RAD51C, and RAD51D[3-4].
In vitro, pretreatment of A549 cells with AZD5305 (1-100nM) for 1 hour, followed by stimulation with H₂O₂ (10mmol/L) for 5 minutes, significantly inhibited PARylation (poly-ADP-ribosylation)[5]. Treatment of U-2 OS cells with AZD5305 (1-100nM) for 24 hours significantly induced S/G2 phase cell cycle arrest[6].
In vivo, daily oral treatment of BRCA1-mutated ovarian cancer patient-derived xenograft (PDX) model mice with AZD5305 (0.1-10mg/kg) for 14 days significantly suppressed the growth of subcutaneous xenografts and induced tumor regression[7]. Daily oral administration of AZD5305 (1mg/kg) to BRCA1/2-mutated breast cancer PDX model mice for 150 days. AZD5305 significantly induced complete tumor remission and prolonged progression-free survival[8].
References:
[1] Gao S, Hou Y, Xu Y, et al. Discovery of Pyrazolo[1,5,4-de]quinoxalin-2(3H)-one Derivatives as Highly Potent and Selective PARP1 Inhibitors. J Med Chem. 2024 Dec 12;67(23):21380-21399.
[2] Johannes JW, Balazs AYS, Barratt D, et al. Discovery of 6-Fluoro-5-{4-[(5-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl]piperazin-1-yl}-N-methylpyridine-2-carboxamide (AZD9574): A CNS-Penetrant, PARP1-Selective Inhibitor. J Med Chem. 2024 Dec 26;67(24):21717-21728.
[3] Kinneer K, Wortmann P, Cooper ZA, et al. Design and Preclinical Evaluation of a Novel B7-H4-Directed Antibody-Drug Conjugate, AZD8205, Alone and in Combination with the PARP1-Selective Inhibitor AZD5305. Clin Cancer Res. 2023 Mar 14;29(6):1086-1101.
[4] Zheng J, Li Z, Min W. Current status and future promise of next-generation poly (ADP-Ribose) polymerase 1-selective inhibitor AZD5305. Front Pharmacol. 2023 Jan 23;13:979873.
[5] Illuzzi G, Staniszewska AD, Gill SJ, et al. Preclinical Characterization of AZD5305, A Next-Generation, Highly Selective PARP1 Inhibitor and Trapper. Clin Cancer Res. 2022 Nov 1;28(21):4724-4736.
[6] Pires MJ, Alam S, Lovric A, et al. Duplexed CeTEAM drug biosensors reveal determinants of PARP inhibitor selectivity in cells. J Biol Chem. 2025 Apr;301(4):108361.
[7] Dellavedova G, Decio A, Formenti L, et al. The PARP1 Inhibitor AZD5305 Impairs Ovarian Adenocarcinoma Progression and Visceral Metastases in Patient-derived Xenografts Alone and in Combination with Carboplatin. Cancer Res Commun. 2023 Mar 27;3(3):489-500.
[8] Herencia-Ropero A, Llop-Guevara A, Staniszewska AD, et al. The PARP1 selective inhibitor saruparib (AZD5305) elicits potent and durable antitumor activity in patient-derived BRCA1/2-associated cancer models. Genome Med. 2024 Aug 26;16(1):107.
AZD5305高选择性PARP1抑制剂，通过精准靶向PARP1破坏肿瘤细胞的DNA损伤修复机制，从而诱导癌细胞死亡，AZD5305对PARP1（IC50=3nM）的选择性比PARP2（IC50=1400nM）高约500倍[1-2]。AZD5305可用于治疗携带BRCA1、BRCA2、PALB2、RAD51C或RAD51D等同源重组修复（HRR）基因突变的实体瘤治疗[3-4]。
在体外，AZD5305（1-100nM）预处理A549细胞1小时，随后以H2O2（10mmol/L）刺激5分钟，AZD5305显著抑制PARylation（多聚ADP-核糖基化）[5]。AZD5305（1-100nM）处理U-2 OS细胞24小时，显著诱导S/G2期细胞周期阻滞[6]。
在体内，AZD5305（0.1-10mg/kg）每日口服处理BRCA1突变卵巢癌异种移植（PDX）模型小鼠持续14天，显著抑制皮下移植瘤生长并诱导肿瘤消退[7]。AZD5305（1mg/kg）每日口服处理BRCA1/2突变患者来源乳腺癌PDX模型小鼠，连续治疗150天。AZD5305显著诱导肿瘤完全缓解并延长无进展生存期[8]。