Design, synthesis and biological evaluation of novel HIF-1α PROTACs degrader as potent anti-cervical cancer agents

IF 2.3 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters Pub Date : 2026-02-01 Epub Date: 2025-10-21 DOI:10.1016/j.bmcl.2025.130443

En-Jie Zhu , Xing-Sheng Bu , Ying Yue , Yong-Sheng Hou , Jia-Rong Liu , Tharcisse Gatera , Shu-Yang Ni , Tian Chai , Xing-Rong Wang , Jun-Li Yang

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Abstract

Cervical cancer is the fourth most common and deadly cancer globally. Hypoxia-inducible factor-1α (HIF-1α) plays a key promoter of tumor progression and treatment resistance, making it an important anticancer target. Here, we designed and synthesized a series of novel HIF-1α-targeting PROTAC degraders based on LW-6 and its derivative W-1. Among them, Z12 showed the strongest anti-proliferative and HIF1α degradation activities in HeLa cells. Z12 promoted HIF-1α degradation via the ubiquitin-proteasome pathway by facilitating the formation of a HIF-1α/VHL ternary complex. Furthermore, Z12 inhibited HeLa cell proliferation, migration, and colony formation, induced apoptosis, and reduced p-MEK and p-AKT expression in the MAPK and PI3K/AKT pathways. This work offers a promising strategy for developing HIF1α-PROTAC degraders and treating cervical cancer.

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新型HIF-1α PROTACs降解剂的设计、合成及生物学评价

子宫颈癌是全球第四大最常见和最致命的癌症。缺氧诱导因子-1α (HIF-1α)是肿瘤进展和治疗耐药的关键促进因子，是重要的抗癌靶点。本文以LW-6及其衍生物W-1为基础，设计并合成了一系列新型靶向hif -1α-的PROTAC降解物。其中Z12在HeLa细胞中表现出最强的抗增殖和HIF1α降解活性。Z12通过泛素-蛋白酶体途径促进HIF-1α降解，促进HIF-1α/VHL三元配合物的形成。此外，Z12抑制HeLa细胞的增殖、迁移和集落形成，诱导凋亡，降低MAPK和PI3K/AKT通路中p-MEK和p-AKT的表达。这项工作为开发hif - α- protac降解物和治疗宫颈癌提供了一个有希望的策略。

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

Bioorganic & Medicinal Chemistry Letters 医学-医药化学

CiteScore

5.70

自引率

3.70%

发文量

463

审稿时长

27 days

期刊介绍： Bioorganic & Medicinal Chemistry Letters presents preliminary experimental or theoretical research results of outstanding significance and timeliness on all aspects of science at the interface of chemistry and biology and on major advances in drug design and development. The journal publishes articles in the form of communications reporting experimental or theoretical results of special interest, and strives to provide maximum dissemination to a large, international audience.