胰腺癌是全球癌症相关死亡的前五位主要原因之一，且存活率较低。目前胰腺癌的治疗缺乏肿瘤特异性，导致对正常组织产生有害影响。因此，开发治疗胰腺癌的肿瘤特异性药物至关重要。 NAD(P)H：醌氧化还原酶 1 (NQO1) 在胰腺癌中高表达，但在正常组织中不表达，这使得 NQO1 生物可激活药物成为选择性杀死 NQO1 阳性癌细胞的潜在疗法。我们之前的研究表明，新型 NQO1 生物激活药物脱氧苯醌 (DNQ) 杀死 NQO1 阳性癌细胞的能力比原型 NQO1 生物激活药物 β-拉帕酮强十倍。然而，DNQ 治疗会导致高级别高铁血红蛋白血症，这是一种限制临床发展的显着副作用。在这里，我们首次报道了 DNQ 衍生物异戊基脱氧苯醌 (IP-DNQ)，它以 NQO1 依赖性方式选择性杀死胰腺导管腺癌细胞，其效力与母体 DNQ 相同。 IP-DNQ 会引起大量 ROS 产生和氧化性 DNA 损伤，导致 PARP1 过度激活、线粒体灾难和 G2/M 期停滞，从而导致细胞凋亡和坏死性程序性细胞死亡。重要的是，IP-DNQ治疗在体内引起轻度高铁血红蛋白血症，与DNQ相比，最大耐受剂量提高了三倍，同时在皮下和原位胰腺癌异种移植模型中显着抑制肿瘤生长并延长小鼠的寿命。我们的研究表明，IP-DNQ 是治疗 NQO1 阳性胰腺癌的一种有前景的疗法，并可能增强其他抗癌药物的疗效。 IP-DNQ 代表了一种治疗胰腺癌的新方法，有可能改善患者的预后。

Pancreatic cancer is among the top five leading causes of cancer-related deaths worldwide, with low survival rates. Current therapies for pancreatic cancer lack tumor specificity, resulting in harmful effects on normal tissues. Therefore, developing tumor-specific agents for the treatment of pancreatic cancer is critical. NAD(P)H:quinone oxidoreductase 1 (NQO1), highly expressed in pancreatic cancers but not in normal tissues, makes NQO1 bioactivatable drugs a potential therapy for selectively killing NQO1-positive cancer cells. Our previous studies have revealed that novel NQO1 bioactivatable drug deoxynyboquinone (DNQ) is ten-fold more potent than the prototypic NQO1 bioactivatable drug β-lapachone in killing of NQO1-positive cancer cells. However, DNQ treatment results in high-grade methemoglobinemia, a significant side effect that limits clinical development. Here, we report for the first time on a DNQ derivative, isopentyl-deoxynboquinone (IP-DNQ), which selectively kills pancreatic ductal adenocarcinoma cells in an NQO1-dependent manner with equal potency to the parent DNQ. IP-DNQ evokes massive ROS production and oxidative DNA lesions that results in PARP1 hyperactivation, mitochondrial catastrophe and G2/M-phase arrest, leading to apoptotic and necrotic programmed cell death. Importantly, IP-DNQ treatment causes mild methemoglobinemia in vivo, with a three-fold improvement in the maximum tolerated dose compared to DNQ, while significantly suppresses tumor growth and extends the lifespan of mice in subcutaneous and orthotopic pancreatic cancer xenograft models. Our study demonstrates that IP-DNQ is a promising therapy for NQO1-positive pancreatic cancers and may enhance the efficacy of other anticancer drugs. IP-DNQ represents a novel approach to treating pancreatic cancer with the potential to improve patient outcomes.