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(5H)-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 engageme READ ARTICLE
Journal of Medicinal Chemistry DOI:10.1021/acs.jmedchem.8b01947
Authors: Ellen Watts, David Heidenreich, Elizabeth Tucker, Monika Raab, Klaus Strebhardt, Louis Chesler, Stefan Knapp, Benjamin Bellenie, and Swen Hoelder