Citation: Wei Yan, Naizhen Zhang, Xiao Liu, Qiyu He, Xucheng Lv, Jianghui Sun, Lili Zhuang, Yuexin Zou, Yajie Zhang, Yuhang Liang, Yanjie Wang, Siyuan Li, Yonghui Sun. Development of visible-light photocaged molecular glues (vc-MGs) for B-cell malignancies therapy with improved safety and pharmacokinetic profiles in vivo[J]. Chinese Chemical Letters, ;2026, 37(5): 112064. doi: 10.1016/j.cclet.2025.112064 shu

Development of visible-light photocaged molecular glues (vc-MGs) for B-cell malignancies therapy with improved safety and pharmacokinetic profiles in vivo

Wei Yan ^{a, b, 1} ,
Naizhen Zhang ^{a, b, 1} ,
Xiao Liu ^{a, b, 1} ,
Qiyu He ^{a, b} ,
Xucheng Lv ^a ,
Jianghui Sun ^{a, b} ,
Lili Zhuang ^{a, b} ,
Yuexin Zou ^{a, b} ,
Yajie Zhang ^{a, b} ,
Yuhang Liang ^a ,
Yanjie Wang ^a ,
Siyuan Li ^a ,
Yonghui Sun ^{a, b, *,}

a.
State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China
b.
Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China

sunyonghui@imm.ac.cn

Received Date: 9 September 2025
Revised Date: 3 November 2025
Accepted Date: 4 November 2025
Available Online: 5 November 2025

Figures(5)

Molecular glues (MGs) represent a promising approach in protein regulation, especially for "undruggable" targets. Despite the advantages over traditional protein inhibitors and proteolysis-targeting chimeras (PROTACs), MGs show various off-target effects, inducing general toxicities in patients. Herein, we describe a structure-guided design of visible-light photocaged MGs (vc-MGs), which precisely and spatiotemporally control the G1 to S phase transition 1 (GSPT1) protein level and Burkitt's lymphoma through visible-light irradiation in vitro and in vivo. Notably, activated VL-MG-9 showed a potent antitumor effect in the RAMOS xenograft mouse model, while VL-MG-9 alone has no GSPT1 degradation activity or general toxicity in various organs even at high dose. Furthermore, proteomics assay and apoptosis analysis confirmed the selectivity and safety of VL-MG-9. Significantly, pharmacokinetic results demonstrated the enhanced permeability and bioavailability (F%) of VL-MG-9. These data clearly reveal the practicality and importance of vc-MGs as preliminary tool for the targeted therapy of malignancies with reduced systemic toxicity and improved druggability.
- Molecular glues,
- Visible-light photocage,
- Burkitt's lymphoma,
- General toxicity,
- Druggability
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