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PDBsum entry 4nwm
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Transferase/transferase inhibitor
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PDB id
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4nwm
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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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Crystal structure of bruton agammaglobulinemia tyrosine kinase complexed with bms-809959 aka 4-tert-butyl-n-[2-me thyl-3-(6-{[4- (morpholine-4-carbonyl)phenyl]amino}-9h- purin-2-yl)phenyl]benzamide
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Structure:
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Tyrosine-protein kinase btk. Chain: a, b. Fragment: unp residues 396-657. Synonym: agammaglobulinemia tyrosine kinase, atk, b-cell progenitor kinase, bpk, bruton tyrosine kinase. Engineered: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: btk, agmx1, atk, bpk. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108.
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Resolution:
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2.03Å
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R-factor:
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0.197
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R-free:
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0.235
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Authors:
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J.K.Muckelbauer
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Key ref:
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Q.Shi
et al.
(2014).
Purine derivatives as potent Bruton's tyrosine kinase (BTK) inhibitors for autoimmune diseases.
Bioorg Med Chem Lett,
24,
2206-2211.
PubMed id:
DOI:
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Date:
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06-Dec-13
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Release date:
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02-Apr-14
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PROCHECK
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Headers
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References
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Q06187
(BTK_HUMAN) -
Tyrosine-protein kinase BTK from Homo sapiens
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Seq:
Struc:
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659 a.a.
262 a.a.*
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Key: |
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Secondary structure |
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CATH domain |
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*
PDB and UniProt seqs differ
at 2 residue positions (black
crosses)
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Enzyme class:
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E.C.2.7.10.2
- non-specific 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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Bioorg Med Chem Lett
24:2206-2211
(2014)
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PubMed id:
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Purine derivatives as potent Bruton's tyrosine kinase (BTK) inhibitors for autoimmune diseases.
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Q.Shi,
A.Tebben,
A.J.Dyckman,
H.Li,
C.Liu,
J.Lin,
S.Spergel,
J.R.Burke,
K.W.McIntyre,
G.C.Olini,
J.Strnad,
N.Surti,
J.K.Muckelbauer,
C.Chang,
Y.An,
L.Cheng,
Q.Ruan,
K.Leftheris,
P.H.Carter,
J.Tino,
G.V.De Lucca.
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ABSTRACT
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Investigation of various heterocyclic core isosteres of imidazopyrazines 1 &
2 yielded purine derivatives 3 & 8 as potent and selective BTK inhibitors.
Subsequent SAR studies of the purine series led to the discovery of 20 as a
leading compound. Compound 20 is very selective when screened against a panel of
400 kinases and is a potent inhibitor in cellular assays of human B cell
function including B-Cell proliferation and CD86 cell surface expression and
exhibited in vivo efficacy in a mouse PCA model. Its X-ray co-crystal structure
with BTK shows that the high selectivity is gained from filling a BTK specific
lipophilic pocket. However, physical and ADME properties leading to low oral
exposure hindered further development.
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Links
