 |
PDBsum entry 5d11
|
|
|
|
References listed in PDB file
|
 |
|
Key reference
|
|
|
Title
|
|
Targeting drug resistance in egfr with covalent inhibitors: a structure-Based design approach.
|
|
|
Authors
|
|
J.Engel,
A.Richters,
M.Getlik,
S.Tomassi,
M.Keul,
M.Termathe,
J.Lategahn,
C.Becker,
S.Mayer-Wrangowski,
C.Grütter,
N.Uhlenbrock,
J.Krüll,
N.Schaumann,
S.Eppmann,
P.Kibies,
F.Hoffgaard,
J.Heil,
S.Menninger,
S.Ortiz-Cuaran,
J.M.Heuckmann,
V.Tinnefeld,
R.P.Zahedi,
M.L.Sos,
C.Schultz-Fademrecht,
R.K.Thomas,
S.M.Kast,
D.Rauh.
|
|
|
Ref.
|
|
J Med Chem, 2015,
58,
6844-6863.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
Abstract
|
|
|
Receptor tyrosine kinases represent one of the prime targets in cancer therapy,
as the dysregulation of these elementary transducers of extracellular signals,
like the epidermal growth factor receptor (EGFR), contributes to the onset of
cancer, such as non-small cell lung cancer (NSCLC). Strong efforts were directed
to the development of irreversible inhibitors and led to compound CO-1686, which
takes advantage of increased residence time at EGFR by alkylating Cys797 and
thereby preventing toxic effects. Here, we present a structure-based approach,
rationalized by subsequent computational analysis of conformational ligand
ensembles in solution, to design novel and irreversible EGFR inhibitors based on
a screening hit that was identified in a phenotype screen of 80 NSCLC cell lines
against approximately 1500 compounds. Using protein X-ray crystallography, we
deciphered the binding mode in engineered cSrc (T338M/S345C), a validated model
system for EGFR-T790M, which constituted the basis for further rational design
approaches. Chemical synthesis led to further compound collections that revealed
increased biochemical potency and, in part, selectivity toward mutated (L858R
and L858R/T790M) vs nonmutated EGFR. Further cell-based and kinetic studies were
performed to substantiate our initial findings. Utilizing proteolytic digestion
and nano-LC-MS/MS analysis, we confirmed the alkylation of Cys797.
|
|
|
|
|
|
|
