Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, P. R. China.
State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry & Pharmacy, Guangxi Normal University, Guilin, Guangxi 541004, P. R. China.
J Am Chem Soc. 2022 Jun 15;144(23):10407-10416. doi: 10.1021/jacs.2c02435. Epub 2022 Jun 3.
Clinical chemotherapeutic drugs have occasionally been observed to induce antitumor immune responses beyond the direct cytotoxicity. Such effects are coined as immunogenic cell death (ICD), representing a "second hit" from the host immune system to tumor cells. Although chemo-immunotherapy is highly promising, ICD inducers remain sparse with vague drug-target mechanisms. Here, we report an endoplasmic reticulum stress-inducing cyclometalated Ir(III)-bisNHC complex () as a new ICD inducer, and based on this compound, a clickable photoaffinity probe was designed for target identification, which unveiled the engagement of the master regulator protein BiP (binding immunoglobulin protein)/GRP78 of the unfolded protein response pathway. This has been confirmed by a series of cellular and biochemical studies including fluorescence microscopy, cellular thermal shift assay, enzymatic assays, and so forth, showing the capability of for BiP destabilization. Notably, besides , the previously reported ICD inducers including KP1339, mitoxantrone, and oxaliplatin were also found to engage BiP interaction, suggesting the important role of BiP in eliciting anticancer immunity. We believe that the ICD-related target information in this work will help to understand the mode of action of ICD that is beneficial to designing new ICD agents with high specificity and improved efficacy.
临床化疗药物偶尔被观察到能在直接细胞毒性之外诱导抗肿瘤免疫反应。这种效应被称为免疫原性细胞死亡（ICD），代表宿主免疫系统对肿瘤细胞的“二次打击”。尽管化疗免疫疗法极具前景，但 ICD 诱导剂仍然稀缺，药物靶点机制也不明确。在这里，我们报告了一种内质网应激诱导的环金属铱（III）-双 NHC 配合物（）作为一种新的 ICD 诱导剂，基于该化合物，我们设计了一种可点击的光亲和探针用于靶标鉴定，揭示了未折叠蛋白反应途径的主要调节蛋白 BiP（结合免疫球蛋白蛋白）/GRP78 的参与。这通过一系列细胞和生化研究得到了证实，包括荧光显微镜、细胞热转移分析、酶测定等，显示了化合物 对 BiP 失稳的能力。值得注意的是，除了，之前报道的 ICD 诱导剂，包括 KP1339、米托蒽醌和奥沙利铂，也被发现与 BiP 相互作用，这表明 BiP 在引发抗癌免疫方面的重要作用。我们相信，这项工作中与 ICD 相关的靶标信息将有助于理解 ICD 的作用模式，有利于设计具有高特异性和更高疗效的新型 ICD 药物。
