PDBsum entry 4wiv

Transcription/transcription inhibitor

PDB id: 4wiv

Contents

Protein chain

127 a.a.

Ligands

3P2

EDO ×2

GOL ×2

Waters ×154

PDB id:

4wiv

Name:

Transcription/transcription inhibitor

Title:

Crystal structure of the first bromodomain of human brd4 in complex with a novel inhibitor umb32 (n-tert-butyl-2-[4-(3,5-dimethyl-1,2- oxazol-4-yl) phenyl]imidazo[1,2-a]pyrazin-3-amine)

Structure:

Bromodomain-containing protein 4. Chain: a. Fragment: unp residues 44-168. Synonym: protein hunk1. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: brd4, hunk1. Expressed in: escherichia coli. Expression_system_taxid: 469008.

Resolution:

1.56Å R-factor: 0.171 R-free: 0.201

Authors:

X.Xu,S.Blacklow

Key ref:

M.R.McKeown et al. (2014). Biased multicomponent reactions to develop novel bromodomain inhibitors. J Med Chem, 57, 9019-9027. PubMed id: 25314271 DOI: 10.1021/jm501120z

Date:

26-Sep-14 Release date: 29-Oct-14

Protein chain

O60885  (BRD4_HUMAN) -  Bromodomain-containing protein 4 from Homo sapiens

Seq: 1362 a.a.

Struc: 127 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

Enzyme reactions

• Enzyme class: E.C.?

DOI no: 10.1021/jm501120z

J Med Chem 57:9019-9027 (2014)

PubMed id: 25314271

Biased multicomponent reactions to develop novel bromodomain inhibitors.

M.R.McKeown, D.L.Shaw, H.Fu, S.Liu, X.Xu, J.J.Marineau, Y.Huang, X.Zhang, D.L.Buckley, A.Kadam, Z.Zhang, S.C.Blacklow, J.Qi, W.Zhang, J.E.Bradner.

ABSTRACT

BET bromodomain inhibition has contributed new insights into gene regulation and emerged as a promising therapeutic strategy in cancer. Structural analogy of early methyl-triazolo BET inhibitors has prompted a need for structurally dissimilar ligands as probes of bromodomain function. Using fluorous-tagged multicomponent reactions, we developed a focused chemical library of bromodomain inhibitors around a 3,5-dimethylisoxazole biasing element with micromolar biochemical IC50. Iterative synthesis and biochemical assessment allowed optimization of novel BET bromodomain inhibitors based on an imidazo[1,2-a]pyrazine scaffold. Lead compound 32 (UMB-32) binds BRD4 with a Kd of 550 nM and 724 nM cellular potency in BRD4-dependent lines. Additionally, compound 32 shows potency against TAF1, a bromodomain-containing transcription factor previously unapproached by discovery chemistry. Compound 32 was cocrystallized with BRD4, yielding a 1.56 Å resolution crystal structure. This research showcases new applications of fluorous and multicomponent chemical synthesis for the development of novel epigenetic inhibitors.