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(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 engagement with ALK and BRD4 in cells as well as favorable broad kinase and bromodomain selectivity.
Highlights
Neuroblastoma is a pediatric cancer of neural crest origin and is the most common extracranial solid tumor in childhood.[1]
We demonstrate the compounds’ on-target engagement with anaplastic lymphoma kinase (ALK) and BRD4 in cells as well as favorable broad kinase and bromodomain selectivity
Crizotinib is clinically ineffective in neuroblastoma and many second-generation ALK inhibitors are predicted to be ineffective for neuroblastoma patients harboring the F1174L mutation due to insufficient inhibition of the mutant kinase.[3]
Summary
Neuroblastoma is a pediatric cancer of neural crest origin and is the most common extracranial solid tumor in childhood.[1]. It is increasingly recognized that targeting multiple pathways that support cancer growth and survival is necessary to treat aggressive cancers, provide a more durable response, and overcome resistance.[10] Given the clinical challenge that highrisk neuroblastoma cases pose, combining ALK and BRD4 inhibition may represent an effective therapeutic approach for this high medical need. Combining both ALK and BRD4 inhibition would serve two purposes. We chose the dual polo-like kinase (PLK)1−BRD4 inhibitor BI-2536 as our starting point and investigated if this inhibitor series can be reoptimized to show potent inhibition of mutant (F1174L) ALK kinase, reduced PLK-1 activity while maintaining BRD4 activity, and acceptable kinome selectivity
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