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PDBsum entry 4lrg
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Transcription regulator/inhibitor
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PDB id
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4lrg
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PDB id:
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| Name: |
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Transcription regulator/inhibitor
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Title:
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Structure of brd4 bromodomain 1 with a dimethyl thiophene isoxazole azepine carboxamide
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Structure:
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Bromodomain-containing protein 4. Chain: a. Fragment: bromodomain 1 (unp residues 42-168). Synonym: protein hunk1. Engineered: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: brd4, brd4_human, hunk1. Expressed in: escherichia coli. Expression_system_taxid: 469008.
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Resolution:
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2.21Å
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R-factor:
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0.230
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R-free:
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0.288
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Authors:
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S.Ravichandran,H.Jayaram,F.Poy,V.Gehling,M.Hewitt,R.Vaswani, Y.Leblanc,A.Cote,C.Nasveschuk,A.Taylor,J.-C.Harmange,J.Audia, E.Pardo,S.Joshi,P.Sandy,J.Mertz,R.Sims,L.Bergeron,B.Bryant, S.Yellapuntala,B.S.Nandana,S.Birudukota,B.Albrecht,S.Bellon
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Key ref:
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V.S.Gehling
et al.
(2013).
Discovery, Design, and Optimization of Isoxazole Azepine BET Inhibitors.
Acs Med Chem Lett,
4,
835-840.
PubMed id:
DOI:
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Date:
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19-Jul-13
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Release date:
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07-Aug-13
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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.
128 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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Acs Med Chem Lett
4:835-840
(2013)
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PubMed id:
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Discovery, Design, and Optimization of Isoxazole Azepine BET Inhibitors.
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V.S.Gehling,
M.C.Hewitt,
R.G.Vaswani,
Y.Leblanc,
A.Côté,
C.G.Nasveschuk,
A.M.Taylor,
J.C.Harmange,
J.E.Audia,
E.Pardo,
S.Joshi,
P.Sandy,
J.A.Mertz,
R.J.Sims,
L.Bergeron,
B.M.Bryant,
S.Bellon,
F.Poy,
H.Jayaram,
R.Sankaranarayanan,
S.Yellapantula,
N.Bangalore Srinivasamurthy,
S.Birudukota,
B.K.Albrecht.
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ABSTRACT
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The identification of a novel series of small molecule BET inhibitors is
described. Using crystallographic binding modes of an amino-isoxazole fragment
and known BET inhibitors, a structure-based drug design effort lead to a novel
isoxazole azepine scaffold. This scaffold showed good potency in biochemical and
cellular assays and oral activity in an in vivo model of BET inhibition.
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Links
