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PDBsum entry 5ftq
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PDB id:
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Transferase
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Title:
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Crystal structure of the alk kinase domain in complex with cmpd 17
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Structure:
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Alk tyrosine kinase receptor. Chain: a. Fragment: kinase domain, unp residues 1094-1407. Synonym: anaplastic lymphoma kinase, alk. Engineered: yes
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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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1.70Å
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R-factor:
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0.175
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R-free:
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0.220
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Authors:
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R.Bossi,G.Canevari,M.Fasolini,M.Menichincheri,E.Ardini,P.Magnaghi, N.Avanzi,P.Banfi,L.Buffa,L.Ceriani,M.Colombo,L.Corti,D.Donati, E.Felder,C.Fiorelli,F.Fiorentini,A.Galvani,A.Isacchi,A.Lombardi Borgia,C.Marchionni,M.Nesi,C.Orrenius,A.Panzeri,E.Perrone,E.Pesenti, L.Rusconi,M.B.Saccardo,E.Vanotti,P.Orsini
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Key ref:
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M.Menichincheri
et al.
(2016).
Discovery of Entrectinib: A New 3-Aminoindazole As a Potent Anaplastic Lymphoma Kinase (ALK), c-ros Oncogene 1 Kinase (ROS1), and Pan-Tropomyosin Receptor Kinases (Pan-TRKs) inhibitor.
J Med Chem,
59,
3392-3408.
PubMed id:
DOI:
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Date:
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14-Jan-16
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Release date:
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06-Apr-16
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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.
293 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 1 residue position (black
cross)
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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
59:3392-3408
(2016)
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PubMed id:
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Discovery of Entrectinib: A New 3-Aminoindazole As a Potent Anaplastic Lymphoma Kinase (ALK), c-ros Oncogene 1 Kinase (ROS1), and Pan-Tropomyosin Receptor Kinases (Pan-TRKs) inhibitor.
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M.Menichincheri,
E.Ardini,
P.Magnaghi,
N.Avanzi,
P.Banfi,
R.Bossi,
L.Buffa,
G.Canevari,
L.Ceriani,
M.Colombo,
L.Corti,
D.Donati,
M.Fasolini,
E.Felder,
C.Fiorelli,
F.Fiorentini,
A.Galvani,
A.Isacchi,
A.L.Borgia,
C.Marchionni,
M.Nesi,
C.Orrenius,
A.Panzeri,
E.Pesenti,
L.Rusconi,
M.B.Saccardo,
E.Vanotti,
E.Perrone,
P.Orsini.
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ABSTRACT
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Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase responsible for
the development of different tumor types. Despite the remarkable clinical
activity of crizotinib (Xalkori), the first ALK inhibitor approved in 2011, the
emergence of resistance mutations and of brain metastases frequently causes
relapse in patients. Within our ALK drug discovery program, we identified
compound 1, a novel 3-aminoindazole active on ALK in biochemical and in cellular
assays. Its optimization led to compound 2 (entrectinib), a potent orally
available ALK inhibitor active on ALK-dependent cell lines, efficiently
penetrant the blood-brain barrier (BBB) in different animal species and highly
efficacious in in vivo xenograft models. Moreover, entrectinib resulted to be
strictly potent on the closely related tyrosine kinases ROS1 and TRKs recently
found constitutively activated in several tumor types. Entrectinib is currently
undergoing phase I/II clinical trial for the treatment of patients affected by
ALK-, ROS1-, and TRK-positive tumors.
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Links
