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PDBsum entry 4cmu
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PDB id:
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Transferase
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Title:
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Structure of the human anaplastic lymphoma kinase in complex with the inhibitor (10r)-7-amino-12-fluoro-1,3,10,16-tetramethyl-16,17- dihydro- 1h-8,4-(metheno)pyrazolo(4,3-h)(2,5,11) benzoxadiazacyclotetradecin-15(10h)-one
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Structure:
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Alk tyrosine kinase receptor. Chain: a. Fragment: tyrosine kinase domain, residues 1093-1411. Synonym: anaplastic lymphoma kinase, cd246. Engineered: yes. Other_details: nonphosphorylated
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Expression_system_cell_line: sf9.
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Resolution:
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1.80Å
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R-factor:
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0.206
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R-free:
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0.227
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Authors:
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M.A.Mctigue,Y.L.Deng,W.Liu,A.Brooun,A.E.Stewart
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Key ref:
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T.W.Johnson
et al.
(2014).
Discovery of (10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo[4,3-h][2,5,11]-benzoxadiazacyclotetradecine-3-carbonitrile (PF-06463922), a macrocyclic inhibitor of anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1) with preclinical brain exposure and broad-spectrum potency against ALK-resistant mutations.
J Med Chem,
57,
4720-4744.
PubMed id:
DOI:
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Date:
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17-Jan-14
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Release date:
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28-May-14
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PROCHECK
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Headers
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References
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Q9UM73
(ALK_HUMAN) -
ALK tyrosine kinase receptor from Homo sapiens
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Seq:
Struc:
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1620 a.a.
295 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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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
57:4720-4744
(2014)
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PubMed id:
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Discovery of (10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo[4,3-h][2,5,11]-benzoxadiazacyclotetradecine-3-carbonitrile (PF-06463922), a macrocyclic inhibitor of anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1) with preclinical brain exposure and broad-spectrum potency against ALK-resistant mutations.
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T.W.Johnson,
P.F.Richardson,
S.Bailey,
A.Brooun,
B.J.Burke,
M.R.Collins,
J.J.Cui,
J.G.Deal,
Y.L.Deng,
D.Dinh,
L.D.Engstrom,
M.He,
J.Hoffman,
R.L.Hoffman,
Q.Huang,
R.S.Kania,
J.C.Kath,
H.Lam,
J.L.Lam,
P.T.Le,
L.Lingardo,
W.Liu,
M.McTigue,
C.L.Palmer,
N.W.Sach,
T.Smeal,
G.L.Smith,
A.E.Stewart,
S.Timofeevski,
H.Zhu,
J.Zhu,
H.Y.Zou,
M.P.Edwards.
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ABSTRACT
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Although crizotinib demonstrates robust efficacy in anaplastic lymphoma kinase
(ALK)-positive non-small-cell lung carcinoma patients, progression during
treatment eventually develops. Resistant patient samples revealed a variety of
point mutations in the kinase domain of ALK, including the L1196M gatekeeper
mutation. In addition, some patients progress due to cancer metastasis in the
brain. Using structure-based drug design, lipophilic efficiency, and
physical-property-based optimization, highly potent macrocyclic ALK inhibitors
were prepared with good absorption, distribution, metabolism, and excretion
(ADME), low propensity for p-glycoprotein 1-mediated efflux, and good passive
permeability. These structurally unusual macrocyclic inhibitors were potent
against wild-type ALK and clinically reported ALK kinase domain mutations.
Significant synthetic challenges were overcome, utilizing novel transformations
to enable the use of these macrocycles in drug discovery paradigms. This work
led to the discovery of 8k (PF-06463922), combining broad-spectrum potency,
central nervous system ADME, and a high degree of kinase selectivity.
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