Designing Dual Inhibitors of Anaplastic Lymphoma Kinase (ALK) and Bromodomain-4 (BRD4) by Tuning Kinase Selectivity.
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ICR Authors
Authors
Watts, E
Heidenreich, D
Tucker, E
Raab, M
Strebhardt, K
Chesler, L
Knapp, S
Bellenie, B
Hoelder, S
Heidenreich, D
Tucker, E
Raab, M
Strebhardt, K
Chesler, L
Knapp, S
Bellenie, B
Hoelder, S
Document Type
Journal Article
Date
2019-03
Date Accepted
2019-02-21
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.
Citation
Journal of medicinal chemistry, 2019, 62 (5), pp. 2618 - 2637
Source Title
Publisher
AMER CHEMICAL SOC
ISSN
0022-2623
eISSN
1520-4804
Research Team
Medicinal Chemistry 4 (including Analytical Chemistry)
Paediatric Solid Tumour Biology and Therapeutics
Paediatric Solid Tumour Biology and Therapeutics