Abstract：
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.
摘要：
以前,我们确定AP-1转录因子FOSL1是维持HNSCC中癌症干细胞（CSC）所必需的，和AP-1抑制剂,T-5224，可以消除HNSCCCSCs。然而,它的效力相对较低，而且,T-5224是否通过靶向FOSL1根除CSC，以及FOSL1是否作为消除HNSCC中CSC的有效靶标，需要进一步验证。我们首先发现T-5224可以直接结合FOSL1。作为一个原则证明,使用T-5224作为弹头设计并合成了几种cereblon（CRBN）招募PROTACs，以更有效地靶向FOSL1。顶部化合物可以有效降解HNSCC中的FOSL1，从而有效消除CSC以抑制HNSCC肿瘤发生，与T-5224相比，效力提高了约30到100倍。总之,我们的研究进一步验证了FOSL1是消除HNSCC中CSC的有效靶标,并提示PROTACs可能为开发靶向FOSL1的新型分子提供了独特的分子工具.
