三阴性乳腺癌中靶向BRK1的全碳氢钉接肽的开发

IF 4 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters Pub Date : 2025-07-28 DOI:10.1021/acsmedchemlett.5c00221

Matthew K. Whittaker, Taylor C. Dill, Ameya J. Limaye, Nicholas J. Tsavaris, Nicholas W. Tawadrous and Eileen J. Kennedy*,

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引用次数: 0

摘要

Wiskott-Aldrich综合征蛋白家族（WASF）成员是细胞膜前沿肌动蛋白细胞骨架动力学的关键调节因子。WASF3已被证实在三阴性乳腺癌中直接促进肿瘤的侵袭和转移。WASF3与BRK1、CYFIP1/2、NCKAP1/1L和ABI1/2/3组成异五聚体蛋白复合体，称为WASF调控复合体（WRC），将上游信号通路与arp2 /3介导的肌动蛋白成核连接起来。破坏复合体抑制肌动蛋白重塑，提出了一种针对癌症侵袭和转移的新方法。在这里，我们报道了第一代全碳氢钉接BRK1模拟肽的开发，BASH-2，旨在抑制WRC内BRK1的结合，从而破坏WRC的正常组装和功能。发现BASH-2可渗透细胞，与WASF3和ABI2结合，并以剂量依赖的方式抑制癌细胞的迁移和侵袭。BASH-2可能是一种靶向wasf3促进的三阴性乳腺癌侵袭和转移的新方法。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

Development of an All-Hydrocarbon Stapled Peptide Targeting BRK1 in Triple-Negative Breast Cancer

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Development of an All-Hydrocarbon Stapled Peptide Targeting BRK1 in Triple-Negative Breast Cancer

Wiskott-Aldrich syndrome protein family (WASF) members are key regulators of actin cytoskeleton dynamics at the leading edge of the cell membrane. WASF3 has been demonstrated to directly promote cancer invasion and metastasis in triple-negative breast cancer. WASF3 is incorporated into a heteropentameric protein complex with BRK1, CYFIP1/2, NCKAP1/1L, and ABI1/2/3 termed the WASF Regulatory Complex (WRC) that links upstream signaling pathways to Arp2/3-mediated actin nucleation. Disruption of the complex inhibits actin remodeling and presents a novel approach to targeting cancer invasion and metastasis. Here we report the development of a first-generation all-hydrocarbon stapled BRK1 mimetic peptide, BASH-2, designed to inhibit BRK1 binding within the WRC to disrupt proper WRC assembly and function. BASH-2 was found to permeate cells, bind to WASF3 and ABI2, and inhibit cancer cell migration and invasion in a dose-dependent manner. BASH-2 may present a novel approach to targeting WASF3-promoted invasion and metastasis in triple-negative breast cancer.

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来源期刊

ACS Medicinal Chemistry Letters CHEMISTRY, MEDICINAL-

CiteScore

7.30

自引率

2.40%

发文量

328

审稿时长

1 months

期刊介绍： ACS Medicinal Chemistry Letters is interested in receiving manuscripts that discuss various aspects of medicinal chemistry. The journal will publish studies that pertain to a broad range of subject matter, including compound design and optimization, biological evaluation, drug delivery, imaging agents, and pharmacology of both small and large bioactive molecules. Specific areas include but are not limited to: Identification, synthesis, and optimization of lead biologically active molecules and drugs (small molecules and biologics) Biological characterization of new molecular entities in the context of drug discovery Computational, cheminformatics, and structural studies for the identification or SAR analysis of bioactive molecules, ligands and their targets, etc. Novel and improved methodologies, including radiation biochemistry, with broad application to medicinal chemistry Discovery technologies for biologically active molecules from both synthetic and natural (plant and other) sources Pharmacokinetic/pharmacodynamic studies that address mechanisms underlying drug disposition and response Pharmacogenetic and pharmacogenomic studies used to enhance drug design and the translation of medicinal chemistry into the clinic Mechanistic drug metabolism and regulation of metabolic enzyme gene expression Chemistry patents relevant to the medicinal chemistry field.