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PDBsum entry 5fee
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Transferase/transferase inhibitor
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PDB id
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5fee
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PDB id:
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Transferase/transferase inhibitor
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Title:
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Egfr kinase domain t790m mutant in complex with a covalent aminobenzimidazole inhibitor.
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Structure:
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Epidermal growth factor receptor. Chain: a. Synonym: proto-oncogenE C-erbb-1,receptor tyrosine-protein kinase erbb-1. Engineered: yes. Mutation: yes. Other_details: inhibitor is covalently linked to cys797.
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: egfr, erbb, erbb1, her1. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108.
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Resolution:
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2.70Å
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R-factor:
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0.192
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R-free:
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0.229
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Authors:
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M.Didonato,G.Spraggon
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Key ref:
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G.Lelais
et al.
(2016).
Discovery of (R,E)-N-(7-Chloro-1-(1-[4-(dimethylamino)but-2-enoyl]azepan-3-yl)-1H-benzo[d]imidazol-2-yl)-2-methylisonicotinamide (EGF816), a Novel, Potent, and WT Sparing Covalent Inhibitor of Oncogenic (L858R, ex19del) and Resistant (T790M) EGFR Mutants for the Treatment of EGFR Mutant Non-Small-Cell Lung Cancers.
J Med Chem,
59,
6671-6689.
PubMed id:
DOI:
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Date:
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16-Dec-15
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Release date:
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27-Jul-16
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PROCHECK
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Headers
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References
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P00533
(EGFR_HUMAN) -
Epidermal growth factor receptor from Homo sapiens
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Seq:
Struc:
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1210 a.a.
287 a.a.*
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Key: |
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PfamA domain |
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Secondary structure |
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CATH domain |
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*
PDB and UniProt seqs differ
at 1 residue position (black
cross)
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Enzyme class:
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E.C.2.7.10.1
- receptor protein-tyrosine kinase.
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Reaction:
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L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H+
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L-tyrosyl-[protein]
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+
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ATP
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=
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O-phospho-L-tyrosyl-[protein]
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+
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ADP
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+
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H(+)
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Molecule diagrams generated from .mol files obtained from the
KEGG ftp site
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DOI no:
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J Med Chem
59:6671-6689
(2016)
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PubMed id:
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Discovery of (R,E)-N-(7-Chloro-1-(1-[4-(dimethylamino)but-2-enoyl]azepan-3-yl)-1H-benzo[d]imidazol-2-yl)-2-methylisonicotinamide (EGF816), a Novel, Potent, and WT Sparing Covalent Inhibitor of Oncogenic (L858R, ex19del) and Resistant (T790M) EGFR Mutants for the Treatment of EGFR Mutant Non-Small-Cell Lung Cancers.
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G.Lelais,
R.Epple,
T.H.Marsilje,
Y.O.Long,
M.McNeill,
B.Chen,
W.Lu,
J.Anumolu,
S.Badiger,
B.Bursulaya,
M.DiDonato,
R.Fong,
J.Juarez,
J.Li,
M.Manuia,
D.E.Mason,
P.Gordon,
T.Groessl,
K.Johnson,
Y.Jia,
S.Kasibhatla,
C.Li,
J.Isbell,
G.Spraggon,
S.Bender,
P.Y.Michellys.
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ABSTRACT
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Over the past decade, first and second generation EGFR inhibitors have
significantly improved outcomes for lung cancer patients with activating
mutations in EGFR. However, both resistance through a secondary T790M mutation
at the gatekeeper residue and dose-limiting toxicities from wild-type (WT) EGFR
inhibition ultimately limit the full potential of these therapies to control
mutant EGFR-driven tumors and new therapies are urgently needed. Herein, we
describe our approach toward the discovery of 47 (EGF816, nazartinib), a novel,
covalent mutant-selective EGFR inhibitor with equipotent activity on both
oncogenic and T790M-resistant EGFR mutations. Through molecular docking studies
we converted a mutant-selective high-throughput screening hit (7) into a number
of targeted covalent EGFR inhibitors with equipotent activity across mutants
EGFR and good WT-EGFR selectivity. We used an abbreviated in vivo efficacy study
for prioritizing compounds with good tolerability and efficacy that ultimately
led to the selection of 47 as the clinical candidate.
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Links
