Discovery of a Potent and Highly Isoform-Selective Inhibitor of the Neglected Ribosomal Protein S6 Kinase Beta 2 (S6K2)

The ribosomal protein S6 kinase beta 2 (S6K2) is thought to play an important role in malignant cell proliferation but is understudied compared to its closely related isoform S6 kinase beta 1 (S6K1). To better understand the biological function of S6K2, chemical probes are needed but the high structural homology between S6K2 and S6K1 makes it challenging to selectively address S6K2 with small molecules. We were able to design the first potent and highly isoform-specific S6K2 inhibitor by merging a known S6K1-selective inhibitor with a covalent inhibitor known to engage a cysteine located in the hinge region in the fibroblast growth factor receptor kinase (FGFR) 4 via a nucleophilic aromatic substitution (SNAr) reaction. The title compound shows high selectivity over kinases with an equivalently positioned cysteine as well as in a larger kinase panel. Good stability towards glutathione indicated a non-promiscuous reactivity pattern. Thus, the title compound represents an important step towards a high-quality chemical probe to study S6K2-specific signalling.