Discovery of Pyrimidinediamine Derivatives as Potent Methuosis Inducers for the Treatment of Triple-Negative Breast Cancer.
Discovery of Pyrimidinediamine Derivatives as Potent Methuosis Inducers for the Treatment of Triple-Negative Breast Cancer.
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DOI：
10.1021/acs.jmedchem.3c00090
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发表时间：
2023-05
影响因子：
7.3
通讯作者：
Jia He;Luzhen Wang;Dazhao Mi;Tian Guan;Wenjing Liu;P. He;Haijun Gu;Yuzhan Li;Yangrui Peng;Ai-Qun Jia;Ceshi Chen;Yihua Chen
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文献类型：
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作者：
Jia He;Luzhen Wang;Dazhao Mi;Tian Guan;Wenjing Liu;P. He;Haijun Gu;Yuzhan Li;Yangrui Peng;Ai-Qun Jia;Ceshi Chen;Yihua Chen
三阴性乳腺癌（TNBC）是目前缺乏有效靶向治疗药物的女性中的主要恶性肿瘤，治疗的局限性促使新策略的出现。Methuosis是一种新的空泡呈递细胞死亡模式，促进肿瘤细胞死亡。因此，设计并合成了一系列嘧啶二胺衍生物，通过评价它们抑制TNBC细胞增殖以及诱导对TNBC细胞的杀伤的能力。其中，JH530在TNBC中显示出优异的抗增殖活性和空泡化能力。机理研究表明JH530通过诱导癌细胞凋亡而引起细胞死亡。此外，JH530在HCC 1806异种移植模型中显著抑制肿瘤生长，而体重没有明显降低。总体而言，JH530是一种在体外和体内均表现出显著抑制TNBC生长的方法诱导剂，这为未来开发更多用于TNBC治疗的小分子药物提供了基础。
Triple-negative breast cancer (TNBC) is a leading malignancy among women that currently lack effective targeted therapeutic agents, and the limitations of treatment have prompted the emergence of new strategies. Methuosis is a novel vacuole-presenting cell death modality that promotes tumor cell death. Hence, a series of pyrimidinediamine derivatives were designed and synthesized through evaluation of their abilities that inhibit proliferation as well as induce methuosis against TNBC cells. Among them, JH530 showed excellent anti-proliferative activities and vacuolization capacity in TNBC. The mechanism research indicated that JH530 caused cell death through inducing methuosis of cancer cells. Furthermore, JH530 inhibited tumor growth remarkably in the HCC1806 xenograft model without an apparent decrease in body weight. Overall, JH530 is a methuosis inducer that displayed remarkable suppression of TNBC growth in vitro and in vivo, which provides a basis for the future progress of more small molecules for TNBC treatment.