此前，我们发现 AP-1 转录因子 FOSL1 是维持 HNSCC 中癌症干细胞 (CSC) 所必需的，而 AP-1 抑制剂 T-5224 可以消除 HNSCC CSC。但其效力相对较低，此外，T-5224是否通过靶向FOSL1消除CSC以及FOSL1是否作为消除HNSCC中CSC的有效靶点还需要进一步验证。我们首先发现T-5224可以直接与FOSL1结合。作为原理验证，使用 T-5224 作为弹头设计并合成了几种可招募 cereblon (CRBN) 的 PROTAC，以更有效地瞄准 FOSL1。顶级化合物可以有效降解 HNSCC 中的 FOSL1，从而有效消除 CSC，从而抑制 HNSCC 肿瘤发生，其效力比 T-5224 提高约 30 至 100 倍。总之，我们的研究进一步验证了 FOSL1 作为消除 HNSCC 中 CSC 的有效靶标，并表明 PROTAC 可能为开发针对 FOSL1 的新型分子提供独特的分子工具。版权所有 © 2024 Elsevier Inc. 保留所有权利。

Previously, we identified that AP-1 transcription factor FOSL1 is required to maintain cancer stem cells (CSCs) in HNSCC, and an AP-1 inhibitor, T-5224, can eliminate HNSCC CSCs. However, its potency is relatively low, and furthermore, whether T-5224 eradicates CSCs through targeting FOSL1 and whether FOSL1 serves as an effective target for eliminating CSCs in HNSCC, require further validation. We first found that T-5224 can bind to FOSL1 directly. As a proof-of-principle, several cereblon (CRBN)-recruiting PROTACs were designed and synthesized using T-5224 as a warhead for more effective of targeting FOSL1. The top compound can potently degrade FOSL1 in HNSCC, thereby effectively eliminating CSCs to suppress HNSCC tumorigenesis, with around 30 to 100-fold improved potency over T-5224. In summary, our study further validates FOSL1 as an effective target for eliminating CSCs in HNSCC and suggests that PROTACs may provide a unique molecular tool for the development of novel molecules for targeting FOSL1.Copyright © 2024 Elsevier Inc. All rights reserved.