时间标签：数据日期 2026-10-31 · 生成时间 2026-11-01 05:30（Asia/Shanghai）｜ 检索窗口 PubMed edat 2026/10/28–2026/10/31 ｜ 情报发生日期 2026-10-31
研究问题
However, a persistent concern for PROTACs is undesired and potentially dangerous on-target side effects, where systemic application can impair essential functions in healthy tissue.；Control over the site and timing of activating or inactivating biological regulators is a challenge that has been described as “the Holy Grail of chemical biology and drug discovery”, and requires sophisticated chemical design.；However, 365 nm light penetrates ~0.75 mm in skin, and shifting to 405 nm increases the light penetration depth only to 1 mm.
方法
The same transport, digestion, and data processing procedures detailed above were followed to detect Ru uptake in the zebrafish.；The cells were incubated with the compounds at 37 °C with 5% CO2 for 1 h followed by irradiation with red light for 60 min (58.7 J/cm2).；The media was aspirated, the cell pellets resuspended in 1 mL of ice cold PBS, and transferred to 1.5 mL tubes on ice, then pelleted at 1300 × g for 5 min at 4 °C, aspirated, followed by the addition of lysis buffer (50 mM Tris pH 7.4, 150 mM NaCl, 1% NP40, 0.5% Sodium Deoxycholate, 5 mM NaF, 2 mM sodium orthovanadate, 5 mM sodium pyrophosphate, 5 mM EDTA, 1x G Biosciences protease inhibitor cocktail).；The samples were incubated for 15 min on ice, followed by centrifugation at 19,500 × g for 10 min at 4 °C.
核心结论
A hook effect was observed with 3, which occurred at lower concentrations than seen for dBET1 (for example, at 10 μM for BRD4, but surprisingly, no hook effect was observed for BRD2 and BRD3).；As anticipated, PROTACs that induced BRD4 degradation also reduced c-MYC levels.；Gratifyingly, 3 reduced c-MYC levels more potently than dBET1 (29 vs. 130 nM; Supplementary Figs. and ), and 5 and 6 were much more effective, as they were able to essentially eliminate c-MYC at 10 nM concentrations (Supplementary Figs. , and ). ‖ 结论：More broadly, our findings have implications for all “conditional” systems where activation is induced by any stimuli, and we encourage consideration of the Hill coefficient as a critical determinant of the therapeutic or experimental window, as it can profoundly shape the selectivity and functional range of all prodrugs.
局限
Each has different strengths and limitations.；As a result, traditional PDT agents have the limitation that they are inactive under hypoxia, which is a common feature of most solid tumors.；Given the residual activity or thermal instability of most photocages and photoswitches in the dark, photoactivation with a suitable therapeutic window for selectivity for biological applications, which requires a PI that is ≥100 vide supra, has remained an elusive goal for nearly all reported systems.
对本项目的价值
★★☆☆☆ 营养感知与自噬轴决定「干预窗口 + 剂量方案」，是组合疗法的时间锚。
全文来源
PMC JATS 全文（正文 60,481 字符，已过标题/DOI 逐字归属校验）
原文题录
- 英文标题：RuPHOTACs provide photocontrol over protein degradation with optimized properties for biological applications.
- 期刊与标识：Nat Commun · PMID 42957722 · DOI 10.1038/s41467-026-78110-x
B 级证据分级：B 级（同行评议临床前研究，主要为动物模型）
本文核心结论来自动物模型或体外细胞学，属临床前证据，不能外推至人体。「延长健康寿命」「改善功能」等表述在小鼠中的意义，与人类临床结局之间仍有距离。
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