Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298-0540, United States.
Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298-0540, United States; Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298-0540, United States.
Bioorg Chem. 2024 Oct;151:107613. doi: 10.1016/j.bioorg.2024.107613. Epub 2024 Jul 9.
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.
先前，我们发现 AP-1 转录因子 FOSL1 对于维持头颈部鳞状细胞癌（HNSCC）中的癌症干细胞（CSCs）至关重要，AP-1 抑制剂 T-5224 可以消除 HNSCC 的 CSCs。然而，T-5224 的效力相对较低，此外，T-5224 是否通过靶向 FOSL1 来根除 CSCs，以及 FOSL1 是否是消除 HNSCC 中 CSCs 的有效靶标，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，设计并合成了几种使用 T-5224 作为弹头的 cereblon（CRBN）募集 PROTAC，以更有效地靶向 FOSL1。该顶级化合物可以在 HNSCC 中有效降解 FOSL1，从而有效地消除 CSCs 以抑制 HNSCC 肿瘤发生，其效力比 T-5224 提高了约 30 至 100 倍。总之，我们的研究进一步验证了 FOSL1 是消除 HNSCC 中 CSCs 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。
