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PDBsum entry 5eu1
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Transcription
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PDB id
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5eu1
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PDB id:
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| Name: |
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Transcription
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Title:
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Crystal structure of brd9 in complex with bi-7273
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Structure:
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Brd9. Chain: a, b. Fragment: unp residues 14-134. Synonym: brd9, dkfzp434d0711, dkfzp686l0539, lavs3040, pro9856. Engineered: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562
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Resolution:
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1.60Å
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R-factor:
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0.179
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R-free:
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0.192
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Authors:
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G.Bader,L.M.Martin,S.Steurer,A.Weiss-Puxbaum,A.Zoephel
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Key ref:
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L.J.Martin
et al.
(2016).
Structure-Based Design of an in Vivo Active Selective BRD9 Inhibitor.
J Med Chem,
59,
4462-4475.
PubMed id:
DOI:
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Date:
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18-Nov-15
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Release date:
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09-Mar-16
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PROCHECK
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Headers
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References
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Q9H8M2
(BRD9_HUMAN) -
Bromodomain-containing protein 9 from Homo sapiens
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Seq:
Struc:
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597 a.a.
113 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 10 residue positions (black
crosses)
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DOI no:
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J Med Chem
59:4462-4475
(2016)
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PubMed id:
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Structure-Based Design of an in Vivo Active Selective BRD9 Inhibitor.
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L.J.Martin,
M.Koegl,
G.Bader,
X.L.Cockcroft,
O.Fedorov,
D.Fiegen,
T.Gerstberger,
M.H.Hofmann,
A.F.Hohmann,
D.Kessler,
S.Knapp,
P.Knesl,
S.Kornigg,
S.Müller,
H.Nar,
C.Rogers,
K.Rumpel,
O.Schaaf,
S.Steurer,
C.Tallant,
C.R.Vakoc,
M.Zeeb,
A.Zoephel,
M.Pearson,
G.Boehmelt,
D.McConnell.
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ABSTRACT
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Components of the chromatin remodelling switch/sucrose nonfermentable (SWI/SNF)
complex are recurrently mutated in tumors, suggesting that altering the activity
of the complex plays a role in oncogenesis. However, the role that the
individual subunits play in this process is not clear. We set out to develop an
inhibitor compound targeting the bromodomain of BRD9 in order to evaluate its
function within the SWI/SNF complex. Here, we present the discovery and
development of a potent and selective BRD9 bromodomain inhibitor series based on
a new pyridinone-like scaffold. Crystallographic information on the inhibitors
bound to BRD9 guided their development with respect to potency for BRD9 and
selectivity against BRD4. These compounds modulate BRD9 bromodomain cellular
function and display antitumor activity in an AML xenograft model. Two chemical
probes, BI-7273 (1) and BI-9564 (2), were identified that should prove to be
useful in further exploring BRD9 bromodomain biology in both in vitro and in
vivo settings.
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Links
