6Q3Y

Crystal structure of the first bromodomain of human BRD4 in complex with the inhibitor 16i

Summary for 6Q3Y

• Entry DOI: 10.2210/pdb6q3y/pdb
• Descriptor: Bromodomain-containing protein 4, 1,2-ETHANEDIOL, (7~{R})-2-[[2-ethoxy-4-(1-methylpiperidin-4-yl)phenyl]amino]-7-ethyl-5-methyl-8-(phenylmethyl)-7~{H}-pteridin-6-one, ... (4 entities in total)
• Functional Keywords: brd4(bd1), inhibitor, complex, structural genomics, structural genomics consortium, sgc, gene regulation
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 31724.63

Authors

Heidenreich, D.,Watts, E.,Arrowsmith, C.H.,Bountra, C.,Edwards, A.M.,Knapp, S.,Hoelder, S.,Structural Genomics Consortium (SGC) (deposition date: 2018-12-04, release date: 2019-03-06, Last modification date: 2024-01-24)

Primary citation

Watts, E.,Heidenreich, D.,Tucker, E.,Raab, M.,Strebhardt, K.,Chesler, L.,Knapp, S.,Bellenie, B.,Hoelder, S.
Designing Dual Inhibitors of Anaplastic Lymphoma Kinase (ALK) and Bromodomain-4 (BRD4) by Tuning Kinase Selectivity.
J.Med.Chem., 62:2618-2637, 2019

PubMed Abstract: Concomitant inhibition of anaplastic lymphoma kinase (ALK) and bromodomain-4 (BRD4) is a potential therapeutic strategy for targeting two key oncogenic drivers that co-segregate in a significant fraction of high-risk neuroblastoma patients, mutation of ALK and amplification of MYCN. Starting from known dual polo-like kinase (PLK)-1-BRD4 inhibitor BI-2536, we employed structure-based design to redesign this series toward compounds with a dual ALK-BRD4 profile. These efforts led to compound ( R)-2-((2-ethoxy-4-(1-methylpiperidin-4-yl)phenyl)amino)-7-ethyl-5-methyl-8-((4-methylthiophen-2-yl)methyl)-7,8-dihydropteridin-6(5 H)-one (16k) demonstrating improved ALK activity and significantly reduced PLK-1 activity, while maintaining BRD4 activity and overall kinome selectivity. We demonstrate the compounds' on-target engagement with ALK and BRD4 in cells as well as favorable broad kinase and bromodomain selectivity.

PubMed: 30789735
DOI: 10.1021/acs.jmedchem.8b01947

Experimental method

X-RAY DIFFRACTION (1.2 Å)