Novel proteolysis-targeting chimera targeting RAD51 for the treatment of triple-negative breast cancer.

IF 2 4区 医学 Q3 PHYSIOLOGY
Journal of Physiology and Pharmacology Pub Date : 2025-04-01 Epub Date: 2025-05-05 DOI:10.26402/jpp.2025.2.09
S Kim, I Hwang, D S Kim, Y J Choi, E-B Jeung
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引用次数: 0

Abstract

Triple-negative breast cancer (TNBC) is a highly aggressive subtype characterized by the absence of estrogen receptors, progesterone receptors, and human epidermal growth factor receptor 2. RAD51 is associated with homologous recombination repair (HRR), a crucial DNA repair mechanism. This paper reports the development and efficacy of a novel targeted RAD51 degrader compound, TRD2, for treating TNBC. TRD2 is synthesized by linking a RAD51 binder to the ligand of the E3 ligase cereblon (CRBN). The results showed that TRD2 effectively reduces the RAD51 protein levels in TNBC cells and exhibits potent anticancer effects in vitro and in vivo. Mechanistic studies showed that TRD2 induces RAD51 ubiquitination and subsequent proteasomal degradation by binding to CRBN. Furthermore, TRD2 demonstrated significant tumor growth inhibition in a mouse xenograft model of TNBC. These findings highlight the potential of TRD2 as a promising therapeutic approach in TNBC, leveraging Proteolysis-targeting chimera (PROTAC) technology to degrade the overexpressed RAD51 protein selectively. The study emphasizes the importance of targeting DNA damage repair core proteins and suggests that TRD2 could overcome challenges posed by resistance to conventional therapies. Nevertheless, additional experiments will be needed to validate these observations and explore the potential impacts on other proteins and cancer types. Overall, this research introduces a novel strategy for TNBC treatment, addressing the limitations of current therapeutic options.

靶向RAD51的新型蛋白水解嵌合体治疗三阴性乳腺癌。
三阴性乳腺癌(TNBC)是一种高度侵袭性的亚型,其特征是缺乏雌激素受体、孕激素受体和人表皮生长因子受体2。RAD51与同源重组修复(homologous recombination repair, HRR)有关,这是一种重要的DNA修复机制。本文报道了一种新型靶向RAD51降解化合物TRD2治疗TNBC的研制及其疗效。TRD2是通过将RAD51结合物与E3连接酶小脑(CRBN)的配体连接而合成的。结果表明,TRD2可有效降低TNBC细胞中RAD51蛋白水平,并在体外和体内表现出较强的抗癌作用。机制研究表明,TRD2通过与CRBN结合诱导RAD51泛素化和随后的蛋白酶体降解。此外,TRD2在小鼠TNBC异种移植模型中显示出明显的肿瘤生长抑制作用。这些发现突出了TRD2作为TNBC治疗方法的潜力,利用蛋白水解靶向嵌合体(PROTAC)技术选择性地降解过表达的RAD51蛋白。该研究强调了靶向DNA损伤修复核心蛋白的重要性,并表明TRD2可以克服对传统疗法的耐药性带来的挑战。然而,还需要更多的实验来验证这些观察结果,并探索对其他蛋白质和癌症类型的潜在影响。总的来说,本研究提出了一种新的TNBC治疗策略,解决了当前治疗方案的局限性。
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
CiteScore
4.00
自引率
22.70%
发文量
0
审稿时长
6-12 weeks
期刊介绍: Journal of Physiology and Pharmacology publishes papers which fall within the range of basic and applied physiology, pathophysiology and pharmacology. The papers should illustrate new physiological or pharmacological mechanisms at the level of the cell membrane, single cells, tissues or organs. Clinical studies, that are of fundamental importance and have a direct bearing on the pathophysiology will also be considered. Letters related to articles published in The Journal with topics of general professional interest are welcome.
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