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Dual kinase-bromodomain inhibitors for rationally designed polypharmacology

Nature Chemical Biology volume 10, pages 305–312 (2014)Cite this article

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A Corrigendum to this article was published on 18 July 2014

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Abstract

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, structure-activity 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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Figure 1: Discovery of kinase inhibitors that potently cross-react with bromodomains.
Figure 2: BI-2536 and TG-101348 displace BRD4 from chromatin and suppress c-Myc expression.
Figure 3: BRD4 binding modes of BI-2536 and TG-101348.
Figure 4: Structure-activity relationships for dihydropteridinone interactions with kinases and bromodomains and structural comparison of inhibitor binding modes.
Figure 5: Responses of FLT3 inhibitor–sensitive and inhibitor-resistant AML cell lines to TG-101348 and BET inhibitors.
Figure 6: Functional activities of dual kinase-bromodomain inhibitors in primary human cell disease models.

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  • 04 April 2014

    In the version of this paper originally published, funding from the Wellcome Trust to P.F. and S.P. was not acknowledged. The acknowledgments have been corrected in the HTML and PDF versions of the article.

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Acknowledgements

S.M., S.P., P.F., C.W., O.F., S.M. and S.K. are grateful for support by the Structural Genomics Consortium, a registered charity (number 1097737) that receives funds from AbbVie, Boehringer Ingelheim, the Canada Foundation for Innovation, the Canadian Institutes for Health Research, Genome Canada, GlaxoSmithKline, Janssen, Lilly Canada, the Novartis Research Foundation, the Ontario Ministry of Economic Development and Innovation, Pfizer, Takeda and the Wellcome Trust (092809/Z/10/Z). P.F. and S.P. are supported by a Wellcome Trust Career-Development Fellowship (095751/Z/11/Z). This work was supported in part by a grant from the National Cancer Institute (1R01 CA166616-01) to N.P.S. and by a US National Institutes of Health National Cancer Institute grant (T32CA108462-07) to E.A.L. N.P.S. is a Leukemia and Lymphoma scholar in Clinical Research. We thank P. Gallant, T. Wehrman, E.L. Berg and P. Khanna for critically reading the manuscript and for valuable discussions, the KINOMEscan team for measuring inhibitor Kd values, the BioSeek team for performing BioMAP screens and A. Rooks, R. Nepomuceno and B. Belli for performing MV4-11 proliferation assays.

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Author notes

  1. Pietro Ciceri, Susanne Müller and Alison O'Mahony: These authors contributed equally to this work.

Authors and Affiliations

  1. KINOMEscan Division of DiscoveRx Corporation, San Diego, California, USA

    Pietro Ciceri, Jeremy P Hunt, Gabriel Pallares, Lisa M Wodicka & Daniel K Treiber

  2. Nuffield Department of Clinical Medicine, University of Oxford, Structural Genomics Consortium, Oxford, UK

    Susanne Müller, Panagis Filippakopoulos, Sarah Picaud, Christopher Wells & Stefan Knapp

  3. Nuffield Department of Clinical Medicine, University of Oxford, Target Discovery Institute (TDI), Oxford, UK

    Susanne Müller, Oleg Fedorov, Christopher Wells, Sarah Martin & Stefan Knapp

  4. BioSeek Division of DiscoveRx Corporation, San Francisco, California, USA

    Alison O'Mahony

  5. Nuffield Department of Clinical Medicine, University of Oxford, Ludwig Institute for Cancer Research (LICR), Oxford, UK

    Panagis Filippakopoulos & Sarah Picaud

  6. Division of Hematology/Oncology, University of California–San Francisco, San Francisco, California, USA

    Elisabeth A Lasater & Neil P Shah

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  1. Pietro Ciceri
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Contributions

P.C., J.P.H., G.P., O.F., S. Martin and L.M.W. developed in vitro binding assays, executed experiments and interpreted data. S.P. purified protein and prepared co-crystals. P.F. solved and interpreted co-crystal structures and prepared figures. P.C., C.W. and E.A.L. designed, executed and interpreted cell-based assay experiments. A.O. designed and interpreted all BioMAP studies and prepared figures. D.K.T., S.K., N.P.S., A.O. and S. Müller directed the studies and interpreted data. D.K.T. and S.K. wrote the paper with assistance from co-authors.

Corresponding authors

Correspondence to Daniel K Treiber or Stefan Knapp.

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Competing interests

D.K.T., P.C., A.O.M., J.P.H., L.M.W. and G.P. are employees of DiscoveRx Corporation.

Supplementary information

Supplementary Text and Figures

Supplementary Results, Supplementary Figures 1–10 and Supplementary Tables 1–4. (PDF 2519 kb)

Supplementary Data Set 1

Inhibitor library and BRD4(1) screening results (XLSX 49 kb)

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Ciceri, P., Müller, S., O'Mahony, A. et al. Dual kinase-bromodomain inhibitors for rationally designed polypharmacology. Nat Chem Biol 10, 305–312 (2014). https://doi.org/10.1038/nchembio.1471

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