 |
PDBsum entry 4c35
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Transferase/inhibitor
|
PDB id
|
|
|
|
4c35
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
References listed in PDB file
|
|
|
Key reference
|
|
|
Title
|
|
The discovery of potent ribosomal s6 kinase inhibitors by high-Throughput screening and structure-Guided drug design.
|
|
|
Authors
|
|
S.Couty,
I.M.Westwood,
A.Kalusa,
C.Cano,
J.Travers,
K.Boxall,
C.L.Chow,
S.Burns,
J.Schmitt,
L.Pickard,
C.Barillari,
P.C.Mcandrew,
P.A.Clarke,
S.Linardopoulos,
R.J.Griffin,
G.W.Aherne,
F.I.Raynaud,
P.Workman,
K.Jones,
R.L.Van montfort.
|
|
|
Ref.
|
|
Oncotarget, 2013,
4,
1647-1661.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
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.
|
|
|
|
|
|
|
