Designing Dual Inhibitors of Anaplastic Lymphoma Kinase (ALK) and Bromodomain-4 (BRD4) by Tuning Kinase Selectivity.
Ellen WattsDavid HeidenreichElizabeth TuckerMonika RaabKlaus StrebhardtLouis CheslerStefan KnappBenjamin BellenieSwen HoelderPublished in: Journal of medicinal chemistry (2019)
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.
Keyphrases
- advanced non small cell lung cancer
- protein kinase
- tyrosine kinase
- diffuse large b cell lymphoma
- epidermal growth factor receptor
- induced apoptosis
- newly diagnosed
- ejection fraction
- social media
- prognostic factors
- oxidative stress
- transcription factor
- drug delivery
- cell cycle arrest
- endoplasmic reticulum stress
- ionic liquid
- cell death