Abstract:
Targeted therapy remains the future of anti-cancer drug development, owing to the lack of specificity of current treatments which lead to damage in healthy normal tissues. ATR inhibitors have in recent times demonstrated promising clinical potential, and are currently being evaluated in the clinic. However, despite the considerable optimism for clinical success of these inhibitors, reports of associated normal tissues toxicities remain a concern and can compromise their utility. Here, ICT10336 is reported, a newly developed hypoxia-responsive prodrug of ATR inhibitor, AZD6738, which is hypoxia-activated and specifically releases AZD6738 only in hypoxic conditions, in vitro. This hypoxia-selective release of AZD6738 inhibited ATR activation (T1989 and S428 phosphorylation) and subsequently abrogated HIF1a-mediated adaptation of hypoxic cancers cells, thus selectively inducing cell death in 2D and 3D cancer models. Importantly, in normal tissues, ICT10336 is demonstrated to be metabolically stable and less toxic to normal cells than its active parent agent, AZD6738. In addition, ICT10336 exhibited a superior and efficient multicellular penetration ability in 3D tumor models, and selectively eradicated cells at the hypoxic core compared to AZD6738. In summary, the preclinical data demonstrate a new strategy of tumor-targeted delivery of ATR inhibitors with significant potential of enhancing the therapeutic index.
摘要:
靶向治疗仍是抗癌药物发展的未来,由于目前治疗缺乏特异性,导致健康正常组织受损。最近,ATR抑制剂已显示出有希望的临床潜力,目前正在诊所进行评估。然而,尽管对这些抑制剂的临床成功相当乐观,有关正常组织毒性的报告仍然令人担忧,并可能损害其效用。这里,据报道,ICT10336一种新开发的ATR抑制剂的缺氧反应性前药,AZD6738是缺氧激活的,仅在缺氧条件下特异性释放AZD6738,在体外。AZD6738的这种缺氧选择性释放抑制了ATR激活(T1989和S428磷酸化),随后废除了HIF1a介导的低氧癌细胞适应,从而在2D和3D癌症模型中选择性诱导细胞死亡。重要的是,在正常组织中,ICT10336被证明是代谢稳定的,对正常细胞的毒性低于其活性母体试剂,AZD6738.此外,ICT10336在3D肿瘤模型中表现出优异而有效的多细胞穿透能力,与AZD6738相比,在缺氧核心选择性根除细胞。总之,临床前数据证明了肿瘤靶向递送ATR抑制剂的新策略,具有显著提高治疗指数的潜力.