4‐2 VHL‐Recruiting PROTAC Inhibits the Growth and Migration of Triple Negative Breast Cancer Cells by Triggering Pyroptosis Through Fas‐Mediated IL‐17 Signaling

Sep 23, 2026

SND1 is an oncoprotein overexpressed in breast cancer, particularly in triple-negative breast cancer (TNBC). Prior work identified a novel SND1-interacting peptide, 4-2, which kills TNBC cells by inducing SND1 degradation in a proteasome-dependent manner. PROTAC derivatives based on peptide 4-2 were engineered, and 4-2 VHL-recruiting PROTAC achieved markedly higher SND1 degradation and stronger anti-cancer activity. In vivo, the D-isoform suppressed TNBC xenograft growth more effectively than peptide 4-2. Mechanistically, pyroptosis was triggered via Fas-mediated IL-17 signaling.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages16

Reading Time40 min

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Abstract

Introduction

Background on breast cancer and TNBC

Role of SND1 and peptide 4-2

PROTAC technology rationale

Drug Development Research RESEARCH ARTICLE 4‐2 VHL‐Recruiting PROTAC Inhibits the Growth and Migration of Triple Negative Breast Cancer Cells by Triggering Pyroptosis Through Fas‐Mediated IL‐17 Signaling Qiqi Wang1,2 | Qiufeng Huang1 | Huiping Ou1 | Tingting Huang3 | Yunjiao He4 | Peng Li1 1School of Food and Drug, Shenzhen Polytechnic University, Shenzhen, Guangdong, China | 2Shenzhen Hospital, Southern Medical University, Shenzhen, Guangdong, China | 3Department of Clinical Laboratory, Shenzhen Hospital, Southern Medical University, Shenzhen, Guangdong, China | 4Department of Pharmacology, School of Medicine, Southern University of Science and Technology, Shenzhen, China Correspondence: Peng Li ([lipengwd@szpu.edu.cn](lipengwd@szpu.edu.cn)) | Yunjiao He ([heyj@sustech.edu.cn](heyj@sustech.edu.cn)) Received: 2 March 2026 | Revised: 11 June 2026 | Accepted: 19 August 2026 Funding: Guangdong Basic and Applied Basic Research Foundation, Grant/Award Number: 2023A1515110004; Shenzhen Science and Technology Program, Grant/Award Number: 20231127011819001; Scientific Research Startup Fund for Shenzhen High‐Caliber Personnel of SZPT, Grant/Award Number: 6023330007K; Natural Science Foundation of Guangdong Province, China, Grant/Award Number: 2025A1515010074; Research Projects of Department of Education of Guangdong Province, Grant/Award Number: 2025CJPT003 Keywords: 4‐2 VHL PROTAC | breast cancer | Fas | IL‐17 signaling | pyroptosis | SND1 ABSTRACT SND1 is an oncoprotein found to be overexpressed in breast cancer, especially in triple‐negative breast cancer(TNBC) . In our previous study, a novel SND1‐interacting peptide 4‐2 was identified, exhibiting cytotoxicity to TNBC cells by inducing SND1 degradation. This study for the first time demonstrated the degradation of SND1 was proteasome‐dependent. A series of peptide 4‐2 derivatives were constructed using PROTAC technology. Among these, 4‐2 VHL‐recruiting PROTAC showed significantly increased SND1 degradation efficiency and higher anticancer activity to TNBC cells. The in vivo efficacy study suggested the D‐isoform of 4‐2VHL PROTAC suppressed the growth of TNBC cells in xenograft mouse model more effectively than peptide 4‐2. Mechanistically, 4‐2 VHL‐recruiting PROTAC was demonstrated to induce pyroptosis of TNBC cells through Fas‐mediated IL‐17signaling. This study provides a new lead compound for the development of theSND1‐targeted therapy via the proteolysis‐ targeting system. 1 | Introduction According to GLOBOCAN 2022, breast cancer as the most commonly diagnosed cancer and the leading cause of cancer‐ related death in women results in 665,684 deaths in 2022 (Brayet al. 2024) . Traditional treatments for breast cancer include surgery, chemotherapy, radiotherapy, endocrine therapy, targeted therapy, and other related approaches (Waks and Winer 2019). Triple‐negative breast cancer (TNBC) as a subtype of breast cancer most difficult to treat lacks the estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth receptor 2 (HER2) for endocrine therapy and HER2‐targeted therapy. Recent developed molecular targeted therapy utilizes the key molecular signatures of TNBC to initiate potential therapeutic response (Ye et al. 2023; Haque et al. 2021; Sukumar et al. 2021) . For example, sacituzumab govitecan a TROP2 antibody‐drug conjugate effectively increases the median progression‐free survival of TNBC patients from 1.7 to 5.6 months compared to the single‐agent chemotherapy (Bardia et al. 2019) . This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made. © 2026 The Author(s) . Drug Development Research published by Wiley Periodicals LLC. Drug Development Research, 2026; 87:e70377 1 of 16 [https://doi.org/10.1002/

FAQs

What does 4-2 VHL-recruiting PROTAC do in TNBC cells?

It significantly enhances SND1 degradation and increases anticancer activity against TNBC cells.

How is SND1 degradation by peptide 4-2 regulated in the study?

Degradation is proteasome-dependent.

What mechanism links 4-2 VHL-recruiting PROTAC to pyroptosis?

It induces pyroptosis through Fas-mediated IL-17 signaling.

Sep 23, 2026

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