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PDBsum entry 6slg
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PDB id:
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Transferase
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Title:
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Human erk2 with erk1/2 inhibitor, azd0364.
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Structure:
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Mitogen-activated protein kinase 1. Chain: a. Synonym: mapk 1,ert1,extracellular signal-regulated kinase 2,erk-2, map kinase isoform p42,p42-mapk,mitogen-activated protein kinase 2, mapk 2. Engineered: yes. Erk-tide. Chain: b. Engineered: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: mapk1, erk2, prkm1, prkm2. Expressed in: escherichia coli. Expression_system_taxid: 562. Expression_system_taxid: 562
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Resolution:
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1.33Å
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R-factor:
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0.207
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R-free:
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0.228
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Authors:
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J.Breed,C.Phillips
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Key ref:
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R.A.Ward
et al.
(2019).
Discovery of a Potent and Selective Oral Inhibitor of ERK1/2 (AZD0364) That Is Efficacious in Both Monotherapy and Combination Therapy in Models of Nonsmall Cell Lung Cancer (NSCLC).
J Med Chem,
62,
11004-11018.
PubMed id:
DOI:
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Date:
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19-Aug-19
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Release date:
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20-Nov-19
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PROCHECK
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Headers
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References
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P28482
(MK01_HUMAN) -
Mitogen-activated protein kinase 1 from Homo sapiens
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Seq:
Struc:
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360 a.a.
332 a.a.*
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Key: |
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Secondary structure |
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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.2.7.11.24
- mitogen-activated protein kinase.
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Reaction:
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1.
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L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H+
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2.
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L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H+
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L-seryl-[protein]
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+
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ATP
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=
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O-phospho-L-seryl-[protein]
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+
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ADP
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+
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H(+)
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L-threonyl-[protein]
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+
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ATP
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=
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O-phospho-L-threonyl-[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
62:11004-11018
(2019)
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PubMed id:
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Discovery of a Potent and Selective Oral Inhibitor of ERK1/2 (AZD0364) That Is Efficacious in Both Monotherapy and Combination Therapy in Models of Nonsmall Cell Lung Cancer (NSCLC).
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R.A.Ward,
M.J.Anderton,
P.Bethel,
J.Breed,
C.Cook,
E.J.Davies,
A.Dobson,
Z.Dong,
G.Fairley,
P.Farrington,
L.Feron,
V.Flemington,
F.D.Gibbons,
M.A.Graham,
R.Greenwood,
L.Hanson,
P.Hopcroft,
R.Howells,
J.Hudson,
M.James,
C.D.Jones,
C.R.Jones,
Y.Li,
S.Lamont,
R.Lewis,
N.Lindsay,
J.McCabe,
T.McGuire,
P.Rawlins,
K.Roberts,
L.Sandin,
I.Simpson,
S.Swallow,
J.Tang,
G.Tomkinson,
M.Tonge,
Z.Wang,
B.Zhai.
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ABSTRACT
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The RAS/MAPK pathway is a major driver of oncogenesis and is dysregulated in
approximately 30% of human cancers, primarily by mutations in the BRAF or RAS
genes. The extracellular-signal-regulated kinases (ERK1 and ERK2) serve as
central nodes within this pathway. The feasibility of targeting the RAS/MAPK
pathway has been demonstrated by the clinical responses observed through the use
of BRAF and MEK inhibitors in BRAF V600E/K metastatic melanoma; however,
resistance frequently develops. Importantly, ERK1/2 inhibition may have clinical
utility in overcoming acquired resistance to RAF and MEK inhibitors, where
RAS/MAPK pathway reactivation has occurred, such as relapsed BRAF V600E/K
melanoma. We describe our structure-based design approach leading to the
discovery of AZD0364, a potent and selective inhibitor of ERK1 and ERK2. AZD0364
exhibits high cellular potency (IC50 = 6 nM) as well as excellent
physicochemical and absorption, distribution, metabolism, and excretion (ADME)
properties and has demonstrated encouraging antitumor activity in preclinical
models.
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Links
