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PDBsum entry 5fbo
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Transferase/transferase inhibitor
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PDB id
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5fbo
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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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Btk-inhibitor co-structure
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Structure:
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Tyrosine-protein kinase btk. Chain: a. Fragment: protein kinase domain (unp residues 389-659). 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. Expression_system_cell_line: sf21.
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Resolution:
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1.89Å
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R-factor:
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0.212
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R-free:
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0.236
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Authors:
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T.O.Fischmann
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Key ref:
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J.Liu
et al.
(2016).
Discovery of 8-Amino-imidazo[1,5-a]pyrazines as Reversible BTK Inhibitors for the Treatment of Rheumatoid Arthritis.
Acs Med Chem Lett,
7,
198-203.
PubMed id:
DOI:
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Date:
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14-Dec-15
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Release date:
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23-Mar-16
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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.
255 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.2.7.10.2
- 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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Acs Med Chem Lett
7:198-203
(2016)
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PubMed id:
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Discovery of 8-Amino-imidazo[1,5-a]pyrazines as Reversible BTK Inhibitors for the Treatment of Rheumatoid Arthritis.
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J.Liu,
D.Guiadeen,
A.Krikorian,
X.Gao,
J.Wang,
S.B.Boga,
A.B.Alhassan,
Y.Yu,
H.Vaccaro,
S.Liu,
C.Yang,
H.Wu,
A.Cooper,
J.de Man,
A.Kaptein,
K.Maloney,
V.Hornak,
Y.D.Gao,
T.O.Fischmann,
H.Raaijmakers,
D.Vu-Pham,
J.Presland,
M.Mansueto,
Z.Xu,
E.Leccese,
J.Zhang-Hoover,
I.Knemeyer,
C.G.Garlisi,
N.Bays,
P.Stivers,
P.E.Brandish,
A.Hicks,
R.Kim,
J.A.Kozlowski.
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ABSTRACT
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Bruton's tyrosine kinase (BTK) is a Tec family kinase with a well-defined role
in the B cell receptor (BCR) pathway. It has become an attractive kinase target
for selective B cell inhibition and for the treatment of B cell related
diseases. We report a series of compounds based on
8-amino-imidazo[1,5-a]pyrazine that are potent reversible BTK inhibitors with
excellent kinase selectivity. Selectivity is achieved through specific
interactions of the ligand with the kinase hinge and driven by aminopyridine
hydrogen bondings with Ser538 and Asp539, and by hydrophobic interaction of
trifluoropyridine in the back pocket. These interactions are evident in the
X-ray crystal structure of the lead compounds 1 and 3 in the complex with the
BTK enzyme. Our lead compounds show desirable PK profiles and efficacy in the
preclinical rat collagen induced arthritis model.
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Links
