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PDBsum entry 6tfp
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PDB id:
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Transferase
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Title:
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Btk in complex with lou064, a potent and highly selective covalent inhibitor
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Structure:
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Tyrosine-protein kinase btk. Chain: a, b, c, d, e. 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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2.00Å
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R-factor:
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0.187
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R-free:
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0.204
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Authors:
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C.Scheufler,A.Hinniger,S.Gutmann
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Key ref:
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D.Angst
et al.
(2020).
Discovery of LOU064 (Remibrutinib), a Potent and Highly Selective Covalent Inhibitor of Bruton's Tyrosine Kinase.
J Med Chem,
63,
5102-5118.
PubMed id:
DOI:
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Date:
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14-Nov-19
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Release date:
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04-Mar-20
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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.
266 a.a.
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Key: |
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PfamA domain |
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Secondary structure |
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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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J Med Chem
63:5102-5118
(2020)
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PubMed id:
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Discovery of LOU064 (Remibrutinib), a Potent and Highly Selective Covalent Inhibitor of Bruton's Tyrosine Kinase.
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D.Angst,
F.Gessier,
P.Janser,
A.Vulpetti,
R.Wälchli,
C.Beerli,
A.Littlewood-Evans,
J.Dawson,
B.Nuesslein-Hildesheim,
G.Wieczorek,
S.Gutmann,
C.Scheufler,
A.Hinniger,
A.Zimmerlin,
E.G.Funhoff,
R.Pulz,
B.Cenni.
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ABSTRACT
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Bruton's tyrosine kinase (BTK), a cytoplasmic tyrosine kinase, plays a central
role in immunity and is considered an attractive target for treating autoimmune
diseases. The use of currently marketed covalent BTK inhibitors is limited to
oncology indications based on their suboptimal kinase selectivity. We describe
the discovery and preclinical profile of LOU064 (remibrutinib, 25), a
potent, highly selective covalent BTK inhibitor. LOU064 exhibits an exquisite
kinase selectivity due to binding to an inactive conformation of BTK and has the
potential for a best-in-class covalent BTK inhibitor for the treatment of
autoimmune diseases. It demonstrates potent in vivo target occupancy with
an EC90 of 1.6 mg/kg and dose-dependent efficacy in rat
collagen-induced arthritis. LOU064 is currently being tested in phase 2 clinical
studies for chronic spontaneous urticaria and Sjoegren's syndrome.
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Links
