Goryunova Marina, He Yiran, Karakis Carson, Titerina Elizaveta K, Salazar-Puerta Ana I, Tahara Sayumi, Sp Nipin, Thakkar Neil N, Cómbita-Heredia Orlando, Dathathreya Kavya, La Ferlita Alessandro, Xu Yanping, Zhang Zhentao, Pollock Raphael, Gallego-Perez Daniel, Zhu Hua, Hadad Christopher M, Beane Joal D
Department of Surgery, Division of Surgical Oncology, The James Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
Department of Chemistry and Biochemistry, The Ohio State University, Columbus, OH, USA.
Sci Rep. 2025 Jul 2;15(1):22965. doi: 10.1038/s41598-025-07215-y.
IWS1 is a key assembly factor of the RNA polymerase II (RNAPII) elongation complex, and its overexpression is associated with worse outcomes in patients with liposarcoma (LPS). This study aimed to identify compounds that can disrupt the IWS1/Spt6 interaction and assess their biological effects in dedifferentiated LPS (DDLPS). Using the AlphaFold-predicted structure of IWS1, we identified a core binding region (AA 545-694) for its interaction with Spt6. Through molecular modeling and virtual screening, Ketotifen and Desloratadine were predicted as candidate inhibitors. Both were predicted to mimic Spt6 phenylalanine (F217) and disrupt the complex, which was confirmed by co-immunoprecipitation. Functional assays showed that treatment with either compound reduced migration, invasion, and spheroid formation in DDLPS cell lines. Additionally, increased nuclear localization of IWS1 was observed. These findings suggest Ketotifen and Desloratadine as promising inhibitors of the IWS1/Spt6 interaction, with potential applications in reducing the invasive properties of human LPS.
IWS1是RNA聚合酶II（RNAPII）延伸复合物的关键组装因子，其过表达与脂肪肉瘤（LPS）患者的不良预后相关。本研究旨在鉴定能够破坏IWS1/Spt6相互作用的化合物，并评估它们在去分化脂肪肉瘤（DDLPS）中的生物学效应。利用AlphaFold预测的IWS1结构，我们确定了其与Spt6相互作用的核心结合区域（氨基酸545 - 694）。通过分子建模和虚拟筛选，预测酮替芬和地氯雷他定为候选抑制剂。两者均被预测可模拟Spt6苯丙氨酸（F217）并破坏复合物，这通过免疫共沉淀得到证实。功能分析表明，用这两种化合物处理均可降低DDLPS细胞系的迁移、侵袭和球体形成。此外，还观察到IWS1的核定位增加。这些发现表明酮替芬和地氯雷他定是IWS1/Spt6相互作用的有前景的抑制剂，在降低人类LPS的侵袭特性方面具有潜在应用价值。
