The discovery of potent ribosomal S6 kinase inhibitors by high-throughput screening and structure-guided drug design.
Loading...
Embargo End Date
Authors
Couty, S
Westwood, IM
Kalusa, A
Cano, C
Travers, J
Boxall, K
Chow, CL
Burns, S
Schmitt, J
Pickard, L
Barillari, C
McAndrew, PC
Clarke, PA
Linardopoulos, S
Griffin, RJ
Aherne, GW
Raynaud, FI
Workman, P
Jones, K
van Montfort, RLM
Westwood, IM
Kalusa, A
Cano, C
Travers, J
Boxall, K
Chow, CL
Burns, S
Schmitt, J
Pickard, L
Barillari, C
McAndrew, PC
Clarke, PA
Linardopoulos, S
Griffin, RJ
Aherne, GW
Raynaud, FI
Workman, P
Jones, K
van Montfort, RLM
Document Type
Journal Article
Date
2013-08-25
Date Accepted
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.
Citation
Oncotarget, 2013, 4 (10), pp. 1647 - 1661
Source Title
Publisher
IMPACT JOURNALS LLC
ISSN
1949-2553
eISSN
1949-2553
Research Team
Drug Target Discovery
Clinical Pharmacology & Trials (including Drug Metabolism & Pharmacokinetics Group)
Medicinal Chemistry 3
Signal Transduction & Molecular Pharmacology
Hit Discovery & Structural Design
Structure-Based Drug Design
Clinical Pharmacology & Trials (including Drug Metabolism & Pharmacokinetics Group)
Medicinal Chemistry 3
Signal Transduction & Molecular Pharmacology
Hit Discovery & Structural Design
Structure-Based Drug Design