Journal
NATURE CHEMICAL BIOLOGY
Volume 10, Issue 4, Pages 305-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nchembio.1471
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Funding
- National Cancer Institute [1R01 CA166616-01]
- US National Institutes of Health National Cancer Institute [T32CA108462-07]
- Leukemia and Lymphoma scholar in Clinical Research
- Structural Genomics Consortium [1097737]
- AbbVie
- Boehringer Ingelheim
- Canada Foundation for Innovation
- Canadian Institutes for Health Research, Genome Canada
- Novartis Research Foundation
- Ontario Ministry of Economic Development and Innovation
- Pfizer, Takeda and the Wellcome Trust [092809/Z/10/Z]
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Concomitant inhibition of multiple cancer-driving kinases is an established strategy to improve the durability of clinical responses to targeted therapies. The difficulty of discovering kinase inhibitors with an appropriate multitarget profile has, however, necessitated the application of combination therapies, which can pose major clinical development challenges. Epigenetic reader domains of the bromodomain family have recently emerged as new targets for cancer therapy. Here we report that several clinical kinase inhibitors also inhibit bromodomains with therapeutically relevant potencies and are best classified as dual kinase-bromodomain inhibitors. Nanomolar activity on BRD4 by BI-2536 and TG-101348, which are clinical PLK1 and JAK2-FLT3 kinase inhibitors, respectively, is particularly noteworthy as these combinations of activities on independent oncogenic pathways exemplify a new strategy for rational single-agent polypharmacological targeting. Furthermore, structureactivity relationships and co-crystal structures identify design features that enable a general platform for the rational design of dual kinase-bromodomain inhibitors.
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