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PDBsum entry 4pms
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Transferase/transferase inhibitor
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PDB id
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4pms
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PDB id:
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| Name: |
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Transferase/transferase inhibitor
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Title:
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The structure of trka kinase bound to the inhibitor 4-naphthalen-1-yl- 1-[(5-phenyl-1,2,4-oxadiazol-3-yl)methyl]-1h-pyrrolo[3,2-c]pyridine- 2-carboxylic acid
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Structure:
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High affinity nerve growth factor receptor. Chain: a. Fragment: kinase domain (unp residues 501-787). Synonym: neurotrophic tyrosine kinase receptor type 1,trk1- transforming tyrosine kinase protein,tropomyosin-related kinase a, tyrosine kinase receptor,tyrosine kinase receptor a,trk-a,gp140trk, p140-trka. Engineered: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: ntrk1, mtc, trk, trka. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108
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Resolution:
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2.80Å
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R-factor:
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0.168
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R-free:
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0.240
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Authors:
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H.P.Su
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Key ref:
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S.J.Stachel
et al.
(2014).
Maximizing diversity from a kinase screen: identification of novel and selective pan-Trk inhibitors for chronic pain.
J Med Chem,
57,
5800-5816.
PubMed id:
DOI:
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Date:
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22-May-14
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Release date:
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18-Jun-14
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PROCHECK
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Headers
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References
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P04629
(NTRK1_HUMAN) -
High affinity nerve growth factor receptor from Homo sapiens
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Seq:
Struc:
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796 a.a.
283 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 4 residue positions (black
crosses)
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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
57:5800-5816
(2014)
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PubMed id:
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Maximizing diversity from a kinase screen: identification of novel and selective pan-Trk inhibitors for chronic pain.
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S.J.Stachel,
J.M.Sanders,
D.A.Henze,
M.T.Rudd,
H.P.Su,
Y.Li,
K.K.Nanda,
M.S.Egbertson,
P.J.Manley,
K.L.Jones,
E.J.Brnardic,
A.Green,
J.A.Grobler,
B.Hanney,
M.Leitl,
M.T.Lai,
V.Munshi,
D.Murphy,
K.Rickert,
D.Riley,
A.Krasowska-Zoladek,
C.Daley,
P.Zuck,
S.A.Kane,
M.T.Bilodeau.
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ABSTRACT
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We have identified several series of small molecule inhibitors of TrkA with
unique binding modes. The starting leads were chosen to maximize the structural
and binding mode diversity derived from a high throughput screen of our internal
compound collection. These leads were optimized for potency and selectivity
employing a structure based drug design approach adhering to the principles of
ligand efficiency to maximize binding affinity without overly relying on
lipophilic interactions. This endeavor resulted in the identification of several
small molecule pan-Trk inhibitor series that exhibit high selectivity for
TrkA/B/C versus a diverse panel of kinases. We have also demonstrated efficacy
in both inflammatory and neuropathic pain models upon oral dosing. Herein we
describe the identification process, hit-to-lead progression, and binding
profiles of these selective pan-Trk kinase inhibitors.
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Links
