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

Stefan Gerstenecker; Lisa Haarer; Martin Schröder; Mark Kudolo; Martin P Schwalm; Valentin Wydra; Ricardo A M Serafim; Apirat Chaikuad; Stefan Knapp; Stefan Laufer; Matthias Gehringer

doi:10.3390/cancers13205133

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

Cancers (Basel). 2021 Oct 13;13(20):5133. doi: 10.3390/cancers13205133.

Authors

Stefan Gerstenecker¹, Lisa Haarer¹, Martin Schröder^{2

3}, Mark Kudolo¹, Martin P Schwalm^{2

3}, Valentin Wydra¹, Ricardo A M Serafim¹, Apirat Chaikuad^{2

3}, Stefan Knapp^{2

3

4}, Stefan Laufer^{1

5

6}, Matthias Gehringer^{1

5}

Affiliations

¹ Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmaceutical Sciences, Eberhard Karls University Tübingen, 72076 Tübingen, Germany.
² Department of Biochemistry, Chemistry and Pharmacy, Institute for Pharmaceutical Chemistry, Goethe University Frankfurt, 60438 Frankfurt, Germany.
³ Structural Genomics Consortium, Buchmann Institute for Molecular Life Sciences, Goethe University Frankfurt, 60438 Frankfurt, Germany.
⁴ German Translational Cancer Network (DKTK) Site Frankfurt/Mainz, Frankfurt Cancer Institute (FCI), 60596 Frankfurt, Germany.
⁵ Cluster of Excellence iFIT (EXC 2180) 'Image-Guided & Functionally Instructed Tumor Therapies', Eberhard Karls University Tübingen, 72076 Tübingen, Germany.
⁶ Tübingen Center for Academic Drug Discovery, Eberhard Karls University Tübingen, 72076 Tübingen, Germany.

Abstract

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 homolog S6 kinase beta 1 (S6K1). To better understand the biological function of S6K2, chemical probes are needed, but the high similarity 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 from a known S6K1-selective inhibitor, which was merged with a covalent inhibitor engaging a cysteine located in the hinge region in the fibroblast growth factor receptor kinase (FGFR) 4 via a nucleophilic aromatic substitution (S_NAr) reaction. The title compound shows a high selectivity over kinases with an equivalently positioned cysteine, as well as in a larger kinase panel. A good stability towards glutathione and Nα-acetyl lysine indicates a non-promiscuous reactivity pattern. Thus, the title compound represents an important step towards a high-quality chemical probe to study S6K2-specific signaling.

Keywords: RPS6KB2; S6K2; chemical probes; covalent inhibitors; p70S6K2; p70S6Kb; protein kinases.

Abstract

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