7RN2

Crystal structure of the first bromodomain of human BRD4 in complex with SJ001010551-2

Summary for 7RN2

• Entry DOI: 10.2210/pdb7rn2/pdb
• Descriptor: Bromodomain-containing protein 4, 1,2-ETHANEDIOL, 2-[(6S,10S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]-N-[(pyridin-2-yl)methyl]acetamide, ... (4 entities in total)
• Functional Keywords: bromodomain-containing protein 4 isoform long, brd4, bromodomain containing protein 4, mitotic chromosome associated protein, cell cycle
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 15652.46

Authors

Stachowski, T.R.,Fischer, M. (deposition date: 2021-07-28, release date: 2022-08-03, Last modification date: 2023-10-18)

Primary citation

Koravovic, M.,Mayasundari, A.,Tasic, G.,Keramatnia, F.,Stachowski, T.R.,Cui, H.,Chai, S.C.,Jonchere, B.,Yang, L.,Li, Y.,Fu, X.,Hiltenbrand, R.,Paul, L.,Mishra, V.,Klco, J.M.,Roussel, M.F.,Pomerantz, W.C.,Fischer, M.,Rankovic, Z.,Savic, V.
From PROTAC to inhibitor: Structure-guided discovery of potent and orally bioavailable BET inhibitors.
Eur.J.Med.Chem., 251:115246-115246, 2023

PubMed Abstract: An X-ray structure of a CLICK chemistry-based BET PROTAC bound to BRD2(BD2) inspired synthesis of JQ1 derived heterocyclic amides. This effort led to the discovery of potent BET inhibitors displaying overall improved profiles when compared to JQ1 and birabresib. A thiadiazole derived 1q (SJ1461) displayed excellent BRD4 and BRD2 affinity and high potency in the panel of acute leukaemia and medulloblastoma cell lines. A structure of 1q co-crystalised with BRD4-BD1 revealed polar interactions with the AZ/BC loops, in particular with Asn140 and Tyr139, rationalising the observed affinity improvements. In addition, exploration of pharmacokinetic properties of this class of compounds suggest that the heterocyclic amide moiety improves drug-like features. Our study led to the discovery of potent and orally bioavailable BET inhibitor 1q (SJ1461) as a promising candidate for further development.

PubMed: 36898329
DOI: 10.1016/j.ejmech.2023.115246

Experimental method

X-RAY DIFFRACTION (1.05 Å)