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PDBsum entry 4ogi
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Transcription/inhibitor
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PDB id
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4ogi
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PDB id:
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| Name: |
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Transcription/inhibitor
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Title:
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Crystal structure of the first bromodomain of human brd4 in complex with the inhibitor bi-2536
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Structure:
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Bromodomain-containing protein 4. Chain: a, b. Fragment: bromodomain 1 (unp residues 44-168). Synonym: brd4, protein hunk1. Engineered: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: brd4, hunk1. Expressed in: escherichia coli. Expression_system_taxid: 469008.
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Resolution:
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1.73Å
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R-factor:
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0.178
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R-free:
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0.214
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Authors:
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P.Filippakopoulos,S.Picaud,B.Jose,S.Martin,O.Fedorov,F.Von Delft, C.H.Arrowsmith,A.M.Edwards,C.Bountra,S.Knapp,Structural Genomics Consortium (Sgc)
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Key ref:
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P.Ciceri
et al.
(2014).
Dual kinase-bromodomain inhibitors for rationally designed polypharmacology.
Nat Chem Biol,
10,
305-312.
PubMed id:
DOI:
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Date:
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16-Jan-14
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Release date:
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26-Feb-14
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PROCHECK
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Headers
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References
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O60885
(BRD4_HUMAN) -
Bromodomain-containing protein 4 from Homo sapiens
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Seq:
Struc:
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1362 a.a.
127 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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DOI no:
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Nat Chem Biol
10:305-312
(2014)
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PubMed id:
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Dual kinase-bromodomain inhibitors for rationally designed polypharmacology.
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P.Ciceri,
S.Müller,
A.O'Mahony,
O.Fedorov,
P.Filippakopoulos,
J.P.Hunt,
E.A.Lasater,
G.Pallares,
S.Picaud,
C.Wells,
S.Martin,
L.M.Wodicka,
N.P.Shah,
D.K.Treiber,
S.Knapp.
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ABSTRACT
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Concomitant inhibition of multiple cancer-driving kinases is an established
strategy to improve the durability of clinical responses to targeted therapies.
The difficulty of discovering kinase inhibitors with an appropriate multitarget
profile has, however, necessitated the application of combination therapies,
which can pose major clinical development challenges. Epigenetic reader domains
of the bromodomain family have recently emerged as new targets for cancer
therapy. Here we report that several clinical kinase inhibitors also inhibit
bromodomains with therapeutically relevant potencies and are best classified as
dual kinase-bromodomain inhibitors. Nanomolar activity on BRD4 by BI-2536 and
TG-101348, which are clinical PLK1 and JAK2-FLT3 kinase inhibitors,
respectively, is particularly noteworthy as these combinations of activities on
independent oncogenic pathways exemplify a new strategy for rational
single-agent polypharmacological targeting. Furthermore, structure-activity
relationships and co-crystal structures identify design features that enable a
general platform for the rational design of dual kinase-bromodomain inhibitors.
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Links
