Dual GPX4/PARP inhibitor YHD-26 exerts potent antitumor activity against triple-negative breast cancer via ferroptosis and DNA damage synergy.

IF 6.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology Pub Date : 2026-09-04 DOI:10.1016/j.bcp.2026.118433

Honglei Bao, Yupei Lai, Xi Zhao, Weiji Chen, Zixuan Chen, Yaping Guo, Zhendan He, Haiqiang Wu, Dahong Yao

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引用次数: 0

Abstract

Triple-negative breast cancer (TNBC) represents the most aggressive breast cancer subtype, associated with poor prognosis and frequent drug resistance. Ferroptosis refers to an iron-dependent form of non-apoptotic cell death triggered by lipid peroxidation, offering a promising strategy to overcome this resistance. Here, we describe a dual-pharmacophore fusion strategy that hybridizes the electrophilic warhead of a GPX4 inhibitor with the clinical PARP inhibitor niraparib, leading to the design and synthesis of (S)-2-(4-(1-(4-ethynylthiazole-2-carbonyl)piperidin-3-yl)phenyl)-2H-indazole-7-carboxamide (YHD-26), a novel ferroptosis inducer. YHD-26 inhibits PARP (IC₅₀ = 92 nM) and binds GPX4 (KD = 23.4 μM). Mechanistically, YHD-26 exerts potent antiproliferative effects, induces ferroptosis, and impairs DNA damage repair, resulting in G2/M arrest in MDA-MB-468 and 4 T1 cells. In a 4 T1 xenograft mouse model, YHD-26 inhibited GPX4 and PARP, validating its in vivo antitumor efficacy and dual-target engagement. Collectively, YHD-26 represents a novel dual GPX4/PARP inhibitor with therapeutic potential for TNBC.

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双GPX4/PARP抑制剂YHD-26通过铁下垂和DNA损伤协同作用对三阴性乳腺癌具有有效的抗肿瘤活性。

三阴性乳腺癌（TNBC）是最具侵袭性的乳腺癌亚型，预后差，耐药频繁。铁凋亡是指由脂质过氧化引发的铁依赖性非凋亡细胞死亡形式，为克服这种耐药性提供了一种有希望的策略。在这里，我们描述了一种双药效团融合策略，将GPX4抑制剂的亲电性载体与临床PARP抑制剂niraparib杂交，从而设计和合成了(S)-2-（4-（1-（4-乙基噻唑-2-羰基）胡椒苷-3-基）苯基）- 2h -吲唑-7-羧酰胺（YHD-26），一种新型铁死亡诱导剂。YHD-26抑制PARP (IC50 = 92 nM)，结合GPX4 （KD = 23.4 μM）。在机制上，YHD-26发挥强大的抗增殖作用，诱导铁下垂，损害DNA损伤修复，导致MDA-MB-468和4 T1细胞的G2/M阻滞。在4 T1异种移植小鼠模型中，YHD-26抑制GPX4和PARP，验证了其体内抗肿瘤功效和双靶点作用。总的来说，YHD-26代表了一种新型的GPX4/PARP双重抑制剂，具有治疗TNBC的潜力。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Biochemical pharmacology 医学-药学

CiteScore

10.30

自引率

1.70%

发文量

420

审稿时长

17 days

期刊介绍： Biochemical Pharmacology publishes original research findings, Commentaries and review articles related to the elucidation of cellular and tissue function(s) at the biochemical and molecular levels, the modification of cellular phenotype(s) by genetic, transcriptional/translational or drug/compound-induced modifications, as well as the pharmacodynamics and pharmacokinetics of xenobiotics and drugs, the latter including both small molecules and biologics. The journal''s target audience includes scientists engaged in the identification and study of the mechanisms of action of xenobiotics, biologics and drugs and in the drug discovery and development process. All areas of cellular biology and cellular, tissue/organ and whole animal pharmacology fall within the scope of the journal. Drug classes covered include anti-infectives, anti-inflammatory agents, chemotherapeutics, cardiovascular, endocrinological, immunological, metabolic, neurological and psychiatric drugs, as well as research on drug metabolism and kinetics. While medicinal chemistry is a topic of complimentary interest, manuscripts in this area must contain sufficient biological data to characterize pharmacologically the compounds reported. Submissions describing work focused predominately on chemical synthesis and molecular modeling will not be considered for review. While particular emphasis is placed on reporting the results of molecular and biochemical studies, research involving the use of tissue and animal models of human pathophysiology and toxicology is of interest to the extent that it helps define drug mechanisms of action, safety and efficacy.