 |
PDBsum entry 5c7c
|
|
|
|
References listed in PDB file
|
 |
|
Key reference
|
|
|
Title
|
|
Fragment-Based drug discovery targeting inhibitor of apoptosis proteins: discovery of a non-Alanine lead series with dual activity against ciap1 and xiap.
|
|
|
Authors
|
|
G.Chessari,
I.M.Buck,
J.E.Day,
P.J.Day,
A.Iqbal,
C.N.Johnson,
E.J.Lewis,
V.Martins,
D.Miller,
M.Reader,
D.C.Rees,
S.J.Rich,
E.Tamanini,
M.Vitorino,
G.A.Ward,
P.A.Williams,
G.Williams,
N.E.Wilsher,
A.J.Woolford.
|
|
|
Ref.
|
|
J Med Chem, 2015,
58,
6574-6588.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
Abstract
|
|
|
Inhibitor of apoptosis proteins (IAPs) are important regulators of apoptosis and
pro-survival signaling pathways whose deregulation is often associated with
tumor genesis and tumor growth. IAPs have been proposed as targets for
anticancer therapy, and a number of peptidomimetic IAP antagonists have entered
clinical trials. Using our fragment-based screening approach, we identified
nonpeptidic fragments binding with millimolar affinities to both cellular
inhibitor of apoptosis protein 1 (cIAP1) and X-linked inhibitor of apoptosis
protein (XIAP). Structure-based hit optimization together with an analysis of
protein-ligand electrostatic potential complementarity allowed us to
significantly increase binding affinity of the starting hits. Subsequent
optimization gave a potent nonalanine IAP antagonist structurally distinct from
all IAP antagonists previously reported. The lead compound had activity in
cell-based assays and in a mouse xenograft efficacy model and represents a
highly promising start point for further optimization.
|
|
|
|
|
|
|
