Here, based instead on the PDZ2 domain, V020-9974 was identified and demonstrated to target the SDCBP-HSP90 interaction and thus suppress HSP90 Kbu and decrease HSP90 protein stability, subsequently sensitizing ESCC cells to 5-FU treatment in multiple cell and mouse models, providing a potential therapeutic strategy for advanced ESCC. The gene discussed is SDCBP; the disease is esophageal squamous cell carcinoma.