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The discovery of potent ribosomal S6 kinase inhibitors by high-throughput screening and structure-guided drug design

Lookup NU author(s): Dr Celine CanoORCiD, Professor Roger Griffin

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Abstract

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.

Publication metadata

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

Journal: Oncotarget

Year: 2013

Volume: 4

Issue: 10

Pages: 1647-1661

Online publication date: 25/08/2013

Acceptance date: 23/08/2013

Date deposited: 17/11/2015

ISSN (electronic): 1949-2553

Publisher: Impact Journals LLC

URL: http://dx.doi.org/10.18632/oncotarget.1255

DOI: 10.18632/oncotarget.1255

PubMed id: 24072592

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