PDBsum entry 5f1h

Transcription

PDB id: 5f1h

Contents

Protein chains

113 a.a.

Ligands

5U6 ×2

Waters ×208

PDB id:

5f1h

Name:

Transcription

Title:

Crystal structure of the brd9 bromodamian in complex with bi-9564.

Structure:

Bromodomain-containing protein 9. Chain: a, b. Fragment: bromodomain, unp residues 14-134. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

1.82Å R-factor: 0.192 R-free: 0.202

Authors:

G.Bader,L.J.Martin,S.Steurer,A.Weiss-Puxbaum,A.Zoephel

Key ref:

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: 26914985 DOI: 10.1021/acs.jmedchem.5b01865

Date:

30-Nov-15 Release date: 09-Mar-16

Protein chains

Q9H8M2  (BRD9_HUMAN) -  Bromodomain-containing protein 9 from Homo sapiens

Seq: 597 a.a.

Struc: 113 a.a.*

* PDB and UniProt seqs differ at 10 residue positions (black crosses)

DOI no: 10.1021/acs.jmedchem.5b01865

J Med Chem 59:4462-4475 (2016)

PubMed id: 26914985

Structure-Based Design of an in Vivo Active Selective BRD9 Inhibitor.

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.

ABSTRACT

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.