新型TOP1/PARP1双靶点抑制剂的分子构建及抗癌症研究
Molecular Construction and Anti-Bladder Cancer Study of Novel TOP1/PARP1 Dual-Target Inhibitors.
摘要(中文译文)
膀胱癌是一种在全球范围内发病率和死亡率均较高的恶性肿瘤。临床上常使用顺铂、伊立替康和吉西他滨等DNA损伤剂，但其疗效往往受到获得性耐药的限制。一种关键的耐药机制涉及PARP1在药物诱导的DNA单链断裂（SSBs）作用下上调，从而削弱治疗效果。为克服这一障碍，我们设计并合成了一系列TOP1/PARP1双重抑制剂，通过抑制TOP1同时诱导SSBs，并通过抑制PARP1阻断其修复，将可修复的SSBs转化为致死性双链断裂（DSBs）。其中，化合物D5表现出优异的双靶点抑制活性，有效克服顺铂耐药，并在体外和体内均展现出强效的抗肿瘤疗效（TGI = 65.7%）。总体而言，D5是一种有前景的TOP1/PARP1抑制剂，可用于克服对传统DNA损伤性化疗的耐药。
Abstract
Bladder cancer is a malignant tumor with a high incidence and mortality worldwide. Clinically, DNA-damaging agents such as cisplatin, irinotecan, and gemcitabine are commonly used, but their efficacy is often limited by acquired resistance. A key resistance mechanism involves the upregulation of PARP1 in response to drug-induced DNA single-strand breaks (SSBs), which diminishes the therapeutic effect. To overcome this obstacle, we designed and synthesized a series of united TOP1/PARP1 inhibitors that simultaneously induce SSBs via TOP1 inhibition and block their repair via PARP1 inhibition, converting repairable SSBs to lethal double-strand breaks (DSBs). Among these, compound D5 exhibited excellent dual-target inhibitory activity and effectively overcame cisplatin resistance, demonstrating potent antitumor efficacy in vitro and in vivo (TGI = 65.7%). Collectively, D5 represents a promising TOP1/PARP1 inhibitor for overcoming resistance to conventional DNA-damaging chemotherapies.
如何引用
AMA
Wenchao Wang, Dan Li, Jin Liu, Lei Li, Qi Zhang, Facai Zhang, et al. Molecular Construction and Anti-Bladder Cancer Study of Novel TOP1/PARP1 Dual-Target Inhibitors.. Journal of medicinal chemistry. 2026; doi:10.1021/acs.jmedchem.6c01714.
APA
Wenchao Wang, Dan Li, Jin Liu, Lei Li, Qi Zhang, Facai Zhang, et al (2026). Molecular Construction and Anti-Bladder Cancer Study of Novel TOP1/PARP1 Dual-Target Inhibitors.. Journal of medicinal chemistry. https://doi.org/10.1021/acs.jmedchem.6c01714
GB/T 7714
Wenchao Wang, Dan Li, Jin Liu, Lei Li, Qi Zhang, Facai Zhang, et al. Molecular Construction and Anti-Bladder Cancer Study of Novel TOP1/PARP1 Dual-Target Inhibitors.[J]. Journal of medicinal chemistry, 2026 doi:10.1021/acs.jmedchem.6c01714.
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