Lookup NU author(s): Dr Celine Cano,
Professor Roger Griffin
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
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.
Author(s): Couty S, Westwood I, Kalusa A, Cano C, Travers J, Boxall K, Chow C, Burns S, Schmitt J, Pickard P, Barillari C, McAndrew C, Clarke P, Linardopoulos S, Griffin R, Aherne W, Raynaud F, Workman P, Jones K, Montfort R
Publication type: Article
Publication status: Published
Online publication date: 25/08/2013
Acceptance date: 23/08/2013
ISSN (electronic): 1949-2553
Publisher: Impact Journals LLC
PubMed id: 24072592
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