ISDA: 5S9O

Deposition Date 2021-04-01

Release Date 2021-09-29

Last Version Date 2026-02-18

Entry Detail

PDB ID:

5S9O

Keywords:

CELL CYCLE

Title:

CRYSTAL STRUCTURE OF THE HUMAN BRD2 BD1 BROMODOMAIN IN COMPLEX WITH 9-(cyclopropylmethyl)-7-[(2R,6S)-2,6-dimethylmorpholine-4-carbonyl]-3-(3,5-dimethyl-1,2-oxazol-4-yl)-9H-carbazole-1-carboxamide

Biological Source:

Source Organism(s):

Homo sapiens (Taxon ID: 9606)

Expression System(s):

Escherichia coli

Method Details:

Experimental Method:

X-RAY DIFFRACTION

Resolution:

2.49 Å

R-Value Free:

0.20

R-Value Work:

0.17

R-Value Observed:

0.17

Space Group:

I 2 3

Download Validation Report

Macromolecular Entities

Structures with similar UniProt ID

Protein Blast

Polymer Type:polypeptide(L)
Molecule:Bromodomain-containing protei
Chain IDs:A, B
Chain Length:144
Number of Molecules:2
Biological Source:Homo sapiens

UniProt ID:P25440 Pfam ID:PF00439

Ligand Molecules

EDO

YW1

Primary Citation

Discovery and Preclinical Pharmacology of an Oral Bromodomain and Extra-Terminal (BET) Inhibitor Using Scaffold-Hopping and Structure-Guided Drug Design.

Gavai, A.V, Norris, D, Delucca, G, Tortolani, D, Tokarski, J.S, Dodd, D, O'Malley, D, Zhao, Y, Quesnelle, C, Gill, P, Vaccaro, W, Huynh, T, Ahuja, V, Han, W.C, Mussari, C, Harikrishnan, L, Kamau, M, Poss, M, Sheriff, S, Yan, C, Marsilio, F, Menard, K, Wen, M.L, Rampulla, R, Wu, D.R, Li, J, Zhang, H, Li, P, Sun, D, Yip, H, Traeger, S.C, Zhang, Y, Mathur, A, Zhang, H, Huang, C, Yang, Z, Ranasinghe, A, Everlof, G, Raghavan, N, Tye, C.K, Wee, S, Hunt, J.T, Vite, G, Westhouse, R, Lee, F.Y.Show

J.Med.Chem. 64 14247 14265 (2021)

PMID: 34543572 DOI: 10.1021/acs.jmedchem.1c00625

Abstact

Inhibition of the bromodomain and extra-terminal (BET) family of adaptor proteins is an attractive strategy for targeting transcriptional regulation of key oncogenes, such as c-MYC. Starting with the screening hit 1, a combination of structure-activity relationship and protein structure-guided drug design led to the discovery of a differently oriented carbazole 9 with favorable binding to the tryptophan, proline, and phenylalanine (WPF) shelf conserved in the BET family. Identification of an additional lipophilic pocket and functional group optimization to optimize pharmacokinetic (PK) properties culminated in the discovery of 18 (BMS-986158) with excellent potency in binding and functional assays. On the basis of its favorable PK profile and robust in vivo activity in a panel of hematologic and solid tumor models, BMS-986158 was selected as a candidate for clinical evaluation.

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Primary Citation of related structures

Abstact

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