6MOA

C-terminal bromodomain of human BRD2 in complex with 4-(2-cyclopropyl-7-(6-methylquinolin-5-yl)-1H-benzo[d]imidazol-5-yl)-3,5-dimethylisoxazole inhibitor

PDB DOI: https://doi.org/10.2210/pdb6MOA/pdb

Classification: transcription/transcription inhibitor
Organism(s): Homo sapiens
Expression System: Escherichia coli
Mutation(s): No

Deposited: 2018-10-04 Released: 2019-01-23
Deposition Author(s): Lansdon, E.B., Newby, Z.E.R.

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 1.27 Å
R-Value Free: 0.179
R-Value Work: 0.165
R-Value Observed: 0.166

wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

This is version 1.2 of the entry. See complete history.

Literature

Structure-guided discovery of a novel, potent, and orally bioavailable 3,5-dimethylisoxazole aryl-benzimidazole BET bromodomain inhibitor.

Sperandio, D., Aktoudianakis, V., Babaoglu, K., Chen, X., Elbel, K., Chin, G., Corkey, B., Du, J., Jiang, B., Kobayashi, T., Mackman, R., Martinez, R., Yang, H., Zablocki, J., Kusam, S., Jordan, K., Webb, H., Bates, J.G., Lad, L., Mish, M., Niedziela-Majka, A., Metobo, S., Sapre, A., Hung, M., Jin, D., Fung, W., Kan, E., Eisenberg, G., Larson, N., Newby, Z.E.R., Lansdon, E., Tay, C., Neve, R.M., Shevick, S.L., Breckenridge, D.G.

(2019) Bioorg Med Chem 27: 457-469

PubMed: 30606676 Search on PubMed
DOI: https://doi.org/10.1016/j.bmc.2018.11.020
Primary Citation of Related Structures:
6MO7, 6MO8, 6MO9, 6MOA

PubMed Abstract:
The bromodomain and extra-terminal (BET) family of proteins, consisting of the bromodomains containing protein 2 (BRD2), BRD3, BRD4, and the testis-specific BRDT, are key epigenetic regulators of gene transcription and has emerged as an attractive target for anticancer therapy. Herein, we describe the discovery of a novel potent BET bromodomain inhibitor, using a systematic structure-based approach focused on improving potency, metabolic stability, and permeability. The optimized dimethylisoxazole aryl-benzimidazole inhibitor exhibited high potency towards BRD4 and related BET proteins in biochemical and cell-based assays and inhibited tumor growth in two proof-of-concept preclinical animal models.

Organizational Affiliation

Department of Medicinal Chemistry, Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, USA. Electronic address: david.sperandio@r2mpharma.com.

Macromolecule Content

Total Structure Weight: 13.46 kDa
Atom Count: 1,077
Modelled Residue Count: 109
Deposited Residue Count: 110
Unique protein chains: 1

Macromolecules

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(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
Bromodomain-containing protein 2	A	110	Homo sapiens	Mutation(s): 0 Gene Names: BRD2, KIAA9001, RING3
UniProt & NIH Common Fund Data Resources
Find proteins for P25440 (Homo sapiens) Explore P25440 Go to UniProtKB: P25440
PHAROS: P25440 GTEx: ENSG00000204256
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	P25440
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 2 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
JW4 (Subject of Investigation/LOI) Query on JW4 Download Ideal Coordinates CCD File SDF format, chain B [auth A] MOL2 format, chain B [auth A]	B [auth A]	4-(2-cyclopropyl-7-(6-methylquinolin-5-yl)-1H-benzo[d]imidazol-5-yl)-3,5-dimethylisoxazole C₂₅ H₂₂ N₄ O KHQQNXFBTALTQF-UHFFFAOYSA-N		Interactions Focus chain B [auth A] Interactions & Density Focus chain B [auth A]
GOL Query on GOL Download Ideal Coordinates CCD File SDF format, chain C [auth A] MOL2 format, chain C [auth A]	C [auth A]	GLYCEROL C₃ H₈ O₃ PEDCQBHIVMGVHV-UHFFFAOYSA-N		Interactions Focus chain C [auth A] Interactions & Density Focus chain C [auth A]