The discovery of potent ribosomal S6 kinase inhibitors by high-throughput screening and structure-guided drug design.
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.
Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London, SM2 5NG, UK.
Sylvain
S
Couty
Isaac M
IM
Westwood
Andrew
A
Kalusa
Celine
C
Cano
Jon
J
Travers
Kathy
K
Boxall
Chiau Ling
CL
Chow
Sam
S
Burns
Jessica
J
Schmitt
Lisa
L
Pickard
Caterina
C
Barillari
P Craig
PC
McAndrew
Paul A
PA
Clarke
Spiros
S
Linardopoulos
Roger J
RJ
Griffin
G Wynne
GW
Aherne
Florence I
FI
Raynaud
Paul
P
Workman
Keith
K
Jones
Rob L M
RL
van Montfort
D045744:Cell Line, Tumor; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D015195:Drug Design; D057166:High-Throughput Screening Assays / Q000379:methods; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D011993:Recombinant Fusion Proteins / Q000737:chemistry; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy / Q000201:enzymology
D007093:Imidazoles; D047428:Protein Kinase Inhibitors; D011993:Recombinant Fusion Proteins; D038744:Ribosomal Protein S6 Kinases, 90-kDa; D017868:Cyclic AMP-Dependent Protein Kinases