Role of RSK4 small-molecule inhibitors in clear cell renal cell carcinoma
MA Jing
PENG Yang
XU Junpeng
LIU Yixiong
FAN Linni
Abstract：Objective Ribosomal S6 protein kinase 4(RSK4)is highly expressed in clear cell renal cell carcinoma and is associated with prognosis,suggesting that it may be one of the key kinase molecules in the malignant progression of renal cell carcinoma(RCC)and is expected to be a new potential kinase therapeutic target.Methods A small-molecule compound specific to RSK4 was synthesized and screened.Western blotting method was used to detect the activity of substrates such as RSK4 and its downstream glycogen synthase kinase-3β(GSK-3β)and ribosomal protein S6(rpS6)after dosing,and screen out a drug with the strongest inhibitory effect.Transwell and CCK-8 were used to detect the changes in the invasion,migration and proliferation ability of RCC cell lines after dosing.Results We screened three small molecules with strong inhibitory effect on RSK4 from the epidermal grouth factor receptor inhibitor library in the early stage,and obtained five drugs by changing the structure.After screening,in vitro experiments showed that CZ-54 could specifically inhibit the activity of RSK4 and its downstream substrates rpS6 and GSK-3β,and inhibition of RSK4 could significantly reduce the proliferation,invasion and migration of tumor cells.Conclusion RSK4 is highly expressed in RCC,and the specific small-molecule kinase inhibitor CZ-54 can inhibit the expression of RSK4 and its downstream molecules,thereby reducing the proliferation,invasion and migration ability of RCC,which provides a new direction for the treatment of advanced and refractory RCC in clinical practice.
Keywords：renal cell carcinomaRSK4small-molecule kinase inhibitortargeted therapy
Publication Date：2024-07-28
Online Publishing Date：2026-08-26(First online date of this platform, not the publication date of the document)
Pages：5( 800-804 )