Page 36 - 《中国药科大学学报》2025年第4期

学报
432 Journal of China Pharmaceutical University 2025, 56(4): 432 − 443

调控转录因子 GLI1 与 DNA 相互作用的药物研发策略

乔振宇 ，罗永富 ，裴姚烨 ，李向阳 ，陆朦辰 1,2*
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（ 苏州大学苏州医学院药学院, 苏州 215006； 江苏省抗体靶向药物研究重点实验室, 苏州 215006）
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摘 要 Hedgehog（Hh）信号通路是调控胚胎发育中细胞增殖、分化及组织稳态的关键转导系统，其异常激活与基底细胞
癌、髓母细胞瘤等恶性肿瘤的发生发展密切相关。该通路中跨膜蛋白 Smoothened（SMO）抑制剂已获临床批准用于治疗基
底细胞癌，但是获得性耐药突变和旁路信号激活限制了其疗效。胶质瘤相关癌基因同源物 1（glioma-associated oncogene 1,
GLI1）作为 Hh 通路的终末效应转录因子，因在肿瘤中特异性高表达且不易引发补偿性耐药，成为潜力干预靶点。然而，
GLI1 因缺乏明确配体结合口袋、低抑制活性及类药性差，被归类为"难成药"靶点，目前尚无抑制剂进入临床阶段。本综述基
于 GLI1-DNA 相互作用的结构与功能特征，结合结构生物学与化学生物学新进展，系统总结针对转录因子靶点的多维度调控
策略研究进展（如变构调节、蛋白互作干预、靶向诱导蛋白降解等），为突破不可成药靶点的治疗瓶颈提供新范式。
关键词 Hedgehog 信号通路；GLI1-DNA 相互作用；靶向诱导蛋白降解；抗肿瘤药物开发
中图分类号 R979.1 文献标志码 A 文章编号 1000−5048(2025)04−0432−12
doi：10.11665/j.issn.1000−5048.2025061901

引用本文 乔振宇，罗永富，裴姚烨，等. 调控转录因子 GLI1 与 DNA 相互作用的药物研发策略 [J]. 中国药科大学学报，2025，56（4）：
432 − 443.

Cite this article as: QIAO Zhenyu, LUO Yongfu, PEI Yaoye, et al. Therapeutic development strategies for modulating GLI1-DNA
interactions[J]. J China Pharm Univ, 2025, 56(4): 432 − 443.

Therapeutic development strategies for modulating GLI1-DNA interactions
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QIAO Zhenyu , LUO Yongfu , PEI Yaoye , LI Xiangyang , LU Mengchen 1,2*
1 School of Pharmacy, Suzhou Medical College, Soochow University, Suzhou 215006; Jiangsu Provincial Key Laboratory of
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Antibody-Targeted Drug Research, Suzhou 215006, China
Abstract The Hedgehog (Hh) signaling pathway is a critical transduction system regulating cell proliferation,
differentiation, and tissue homeostasis during embryonic development. Its aberrant activation is closely associated
with the pathogenesis of malignancies such as basal cell carcinoma and medulloblastoma. Although Smoothened
(SMO)-targeting inhibitors have received clinical approval, their therapeutic efficacy is limited by acquired
resistance mutation and compensatory pathway activation. Glioma-associated oncogene homolog 1 (GLI1), the
terminal effector transcription factor of the Hh pathway, has emerged as a promising therapeutic target due to its
tumor-specific overexpression and lower propensity for resistance induction. However, GLI1 is classified as an
"undruggable" target due to the absence of well-defined ligand-binding pockets, low inhibitory activity, and poor
drug-like properties. Currently, no GLI1 inhibitor has entered clinical trials. This review systematically analyzes
multidimensional modulation strategies (e.g., allosteric modulation, protein-protein interaction disruption,
targeted protein degradation) for targeting transcription factors, based on the structural and functional features of
GLI1-DNA interaction combined with recent advances in structural biology and chemical biology, offering new
paradigms to overcome therapeutic barriers against undruggable targets.
Key words Hedgehog signaling pathway; GLI1-DNA interaction; targeted protein degradation; antitumor drug
development

收稿日期 2025-06-19 * 通信作者 Tel：15651039631 E-mail：mclu@suda.edu.cn
基金项目 国家自然科学基金面上项目（No.82273768）、江苏省高等学校自然科学研究面上项目（22KJB350010）、姑苏市创新创业
领军人才计划（ZXL2022483）、天然药物活性组分与药效国家重点实验室开放课题（SKLNMKF202311）