5S9Q

CRYSTAL STRUCTURE OF THE FIRST BROMODOMAIN OF HUMAN BRD4 IN COMPLEX WITH 2-(3,5-dimethyl-1,2-oxazol-4-yl)-7-(2-hydroxypropan-2-yl)-9-[(S)-(oxan-4-yl)(phenyl)methyl]-9H-carbazole-4-carboxamide

Summary for 5S9Q

• Entry DOI: 10.2210/pdb5s9q/pdb
• Group deposition: BET (G_1002195)
• Descriptor: Bromodomain-containing protein 4, 2-(3,5-dimethyl-1,2-oxazol-4-yl)-7-(2-hydroxypropan-2-yl)-9-[(S)-(oxan-4-yl)(phenyl)methyl]-9H-carbazole-4-carboxamide, 1,2-ETHANEDIOL, ... (4 entities in total)
• Functional Keywords: bromodomain-containing protein 4 isoform long, brd4, bromodomain containing protein 4, cap, hunk1, mcap, mitotic chromosome associated protein sgc, cell cycle
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 4
• Total formula weight: 63228.86

Authors

Sheriff, S. (deposition date: 2021-04-01, release date: 2021-09-29, Last modification date: 2024-05-22)

Primary citation

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.
Discovery and Preclinical Pharmacology of an Oral Bromodomain and Extra-Terminal (BET) Inhibitor Using Scaffold-Hopping and Structure-Guided Drug Design.
J.Med.Chem., 64:14247-14265, 2021

PubMed Abstract: 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 , a combination of structure-activity relationship and protein structure-guided drug design led to the discovery of a differently oriented carbazole 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 (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.

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

Experimental method

X-RAY DIFFRACTION (1.85 Å)