近日，英国剑桥大学Gonçalo J. L. Bernardes团队实现了通过双组分前药系统合成肿瘤特异性STING激动剂。2025年9月16日出版的《自然-化学》杂种发表了这项成果。

STING的药理激活在癌症治疗中颇具前景。最近的一个趋势是肿瘤特异性或条件性激活的STING激动剂的发展，以提高安全性和有效性。

研究组探索了一种非常规的前药激活策略，用于肿瘤上合成一种强效激动剂。利用MSA2（一种小分子激动剂，在与STING结合之前非共价二聚）的独特机制，研究组发现，在温和的条件和复杂的环境下，具有活性官能团的MSA2类似物容易和选择性地形成共价二聚体。

研究组发现了一对反应，在基于细胞的检测中，这对反应产生了亚摩尔效力的硫醚连接二聚体。将其中一种反应物与自裂解的β-葡糖苷酸部分结合，形成了一种双组分前药系统，该系统几乎只在过表达β-葡糖醛酸酶的肿瘤中形成活性化合物。这些结果举例说明了使用小分子识别从良性前体中现场生成活性化合物。

附：英文原文

Title: Tumour-specific STING agonist synthesis via a two-component prodrug system

Author: Hsu, Nai-Shu, Tang, Cong, Mendes, Raquel V., Labo-Almeida, Carlos, dos Reis, Caio V., Coelho, Ana R., Marques, Marta C., Cabeza Cabrerizo, Mar, Misteli, Roman, Rooney, Timothy P. C., Hyvnen, Marko, Corzana, Francisco, Fior, Rita, Bernardes, Gonalo J. L.

Issue&Volume: 2025-09-16

Abstract: Pharmacological activation of STING holds promise in cancer treatment. A recent trend is the development of tumour-specific or conditionally activated STING agonists for enhanced safety and efficacy. Here we explore an unconventional prodrug activation strategy for on-tumour synthesis of a potent agonist. Leveraging the unique mechanism of MSA2, a small-molecule agonist that dimerizes non-covalently before binding to STING, we showed that its analogues bearing reactive functional groups readily and selectively form covalent dimers under mild conditions and in complex environments. We identified a reacting pair that led to a thioether-linked dimer with submicromolar potency in cell-based assays. Caging one of the reactants with a self-immolative β-glucuronide moiety resulted in a two-component prodrug system that near-exclusively formed the active compounds in tumours overexpressing β-glucuronidase. These results exemplify the use of small-molecule recognition for on-site generation of active compounds from benign precursors.

DOI: 10.1038/s41557-025-01930-9

Source: https://www.nature.com/articles/s41557-025-01930-9