Discovery of novel p90 ribosomal S6 kinase 2 inhibitors for potential cancer treatment through ligand-based and structure-based virtual screening methods

Abstract

The p90 ribosomal S6 kinase 2 (RSK2) belongs to Ser/Thr kinase family which is involved in a variety of cellular processes, such as cell proliferation, survival and transformation. Recent studies suggest that RSK2 also is a critical proliferative signaling effector of oncogenic tyrosine kinases, which represents targeting RSK2 would be a potential anticancer therapy. Therefore, it would have great clinical significance to discover more novel RSK2 inhibitors by using an in silico strategy that combined ligand-based and structure-based virtual screening (VS). Quantitative structure-activity relationship (QSAR) models were developed based on the structures of known RSK2 bioactivity inhibitors and the verified models were used for screening SPECS database. By molecular docking, the virtual hit compounds were further filtered to obtained compounds with strong binding affinity. Finally, 30 molecules were selected and purchased for in vitro inhibition and SPR binding assays after ADMET evaluation. 5 hit compounds exhibited breast cancer or melanoma cell inhibitory activities with IC50 values from 5.7 to 28.4 ​μM, and the following surface plasmon resonance (SPR) assay suggested that 5 compounds showed strong affinity to RSK2 with the KD values in the range 4.76 ​× ​10−6 to 3.17 ​× ​10−7 ​M, wherein, C2 as the most active compound displayed an IC50 of 5.7 ​μM against melanoma, and with an KD of 856 ​nM against RSK2. Therefore, these compounds can provide us a valuable insight for further optimization and development of more potent RSK2 inhibitors.