Bioscience, Oncology R&D, AstraZeneca, Cambridge, United Kingdom.
Oncology Safety, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Cambridge, United Kingdom.
Clin Cancer Res. 2022 Nov 1;28(21):4724-4736. doi: 10.1158/1078-0432.CCR-22-0301.
We hypothesized that inhibition and trapping of PARP1 alone would be sufficient to achieve antitumor activity. In particular, we aimed to achieve selectivity over PARP2, which has been shown to play a role in the survival of hematopoietic/stem progenitor cells in animal models. We developed AZD5305 with the aim of achieving improved clinical efficacy and wider therapeutic window. This next-generation PARP inhibitor (PARPi) could provide a paradigm shift in clinical outcomes achieved by first-generation PARPi, particularly in combination.
AZD5305 was tested in vitro for PARylation inhibition, PARP-DNA trapping, and antiproliferative abilities. In vivo efficacy was determined in mouse xenograft and PDX models. The potential for hematologic toxicity was evaluated in rat models, as monotherapy and combination.
AZD5305 is a highly potent and selective inhibitor of PARP1 with 500-fold selectivity for PARP1 over PARP2. AZD5305 inhibits growth in cells with deficiencies in DNA repair, with minimal/no effects in other cells. Unlike first-generation PARPi, AZD5305 has minimal effects on hematologic parameters in a rat pre-clinical model at predicted clinically efficacious exposures. Animal models treated with AZD5305 at doses ≥0.1 mg/kg once daily achieved greater depth of tumor regression compared to olaparib 100 mg/kg once daily, and longer duration of response.
AZD5305 potently and selectively inhibits PARP1 resulting in excellent antiproliferative activity and unprecedented selectivity for DNA repair deficient versus proficient cells. These data confirm the hypothesis that targeting only PARP1 can retain the therapeutic benefit of nonselective PARPi, while reducing potential for hematotoxicity. AZD5305 is currently in phase I trials (NCT04644068).
我们假设单独抑制和捕获 PARP1 就足以发挥抗肿瘤活性。特别是，我们旨在实现对 PARP2 的选择性，因为在动物模型中已经表明 PARP2 对造血/祖细胞的存活起作用。我们开发了 AZD5305，旨在提高临床疗效和拓宽治疗窗口。这种新一代 PARP 抑制剂（PARPi）可以在第一代 PARPi 所取得的临床结果方面带来范式转变，特别是在联合治疗方面。
在体外，AZD5305 用于 PAR 化抑制、PARP-DNA 捕获和抗增殖能力的测试。在小鼠异种移植和 PDX 模型中测定体内疗效。在大鼠模型中评估单药治疗和联合治疗的血液学毒性潜力。
AZD5305 是一种高效且选择性的 PARP1 抑制剂，对 PARP1 的选择性是 PARP2 的 500 倍。AZD5305 抑制 DNA 修复缺陷细胞的生长，对其他细胞几乎没有影响。与第一代 PARPi 不同，AZD5305 在预测具有临床疗效的暴露量下，对大鼠临床前模型中的血液学参数几乎没有影响。与奥拉帕利 100mg/kg 每日一次相比，每天一次以 0.1mg/kg 及以上剂量治疗的动物模型实现了更深的肿瘤消退，并且具有更长的反应持续时间。
AZD5305 强烈且选择性地抑制 PARP1，导致极好的抗增殖活性和前所未有的 DNA 修复缺陷细胞与正常细胞之间的选择性。这些数据证实了这样一种假设，即仅靶向 PARP1 就可以保留非选择性 PARPi 的治疗益处，同时降低潜在的血液毒性。AZD5305 目前正在进行 I 期临床试验（NCT04644068）。
