The discovery of potent ribosomal S6 kinase inhibitors by high-throughput screening and structure-guided drug design
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Sylvain Couty1,*, Isaac M. Westwood1,2,*, Andrew Kalusa1, Celine Cano3, Jon Travers1, Kathy Boxall1, Chiau Ling Chow1,2, Sam Burns1, Jessica Schmitt1, Lisa Pickard1, Caterina Barillari1,2, P. Craig McAndrew1, Paul A. Clarke1, Spiros Linardopoulos1, Roger J. Griffin3, G. Wynne Aherne1, Florence I. Raynaud1, Paul Workman1, Keith Jones1, Rob L.M. van Montfort1,2
1 Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London, SM2 5NG, UK
2 Division of Structural Biology, The Institute of Cancer Research, London, SW3 6JB, UK
3 Newcastle Cancer Centre, Northern Institute for Cancer Research, School of Chemistry, Bedson Building, Newcastle University, Newcastle upon Tyne, NE1 7RU, UK
* Authors contributed equally to this work
Rob L.M. van Montfort, email:
Keith Jones, email:
Keywords: S6 kinase, P70S6K, cancer, inhibitor, structure-based drug design
Received: August 7, 2013 Accepted: August 23, 2013 Published: August 25, 2013
The ribosomal P70 S6 kinases play a crucial role in PI3K/mTOR regulated signalling pathways and are therefore potential targets for the treatment of a variety of diseases including diabetes and cancer. In this study we describe the identification of three series of chemically distinct S6K1 inhibitors. In addition, we report a novel PKA-S6K1 chimeric protein with five mutations in or near its ATP-binding site, which was used to determine the binding mode of two of the three inhibitor series, and provided a robust system to aid the optimisation of the oxadiazole-substituted benzimidazole inhibitor series. We show that the resulting oxadiazole-substituted aza-benzimidazole is a potent and ligand efficient S6 kinase inhibitor, which blocks the phosphorylation of RPS6 at Ser235/236 in TSC negative HCV29 human bladder cancer cells by inhibiting S6 kinase activity and thus provides a useful tool compound to investigate the function of S6 kinases.
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