Covalent inhibitors of EGFR family protein kinases induce degradation of human Tribbles 2 (TRIB2) pseudokinase in cancer cells.

Foulkes, D. M. et al. (2018) Covalent inhibitors of EGFR family protein kinases induce degradation of human Tribbles 2 (TRIB2) pseudokinase in cancer cells. Science Signaling, 11(549), eaat7951. (doi: 10.1126/scisignal.aat7951) (PMID:30254057) (PMCID:PMC6553640)

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A major challenge associated with biochemical and cellular analysis of pseudokinases is a lack of target-validated small-molecule compounds with which to probe function. Tribbles 2 (TRIB2) is a cancer-associated pseudokinase with a diverse interactome, including the canonical AKT signaling module. There is substantial evidence that human TRIB2 promotes survival and drug resistance in solid tumors and blood cancers and therefore is of interest as a therapeutic target. The unusual TRIB2 pseudokinase domain contains a unique cysteine-rich C-helix and interacts with a conserved peptide motif in its own carboxyl-terminal tail, which also supports its interaction with E3 ubiquitin ligases. We found that TRIB2 is a target of previously described small-molecule protein kinase inhibitors, which were originally designed to inhibit the canonical kinase domains of epidermal growth factor receptor tyrosine kinase family members. Using a thermal shift assay, we discovered TRIB2-binding compounds within the Published Kinase Inhibitor Set (PKIS) and used a drug repurposing approach to classify compounds that either stabilized or destabilized TRIB2 in vitro. TRIB2 destabilizing agents, including the covalent drug afatinib, led to rapid TRIB2 degradation in human AML cancer cells, eliciting tractable effects on signaling and survival. Our data reveal new drug leads for the development of TRIB2-degrading compounds, which will also be invaluable for unraveling the cellular mechanisms of TRIB2-based signaling. Our study highlights that small molecule-induced protein down-regulation through drug "off-targets" might be relevant for other inhibitors that serendipitously target pseudokinases. [Abstract copyright: Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.]

Item Type:Articles
Additional Information:This work was funded by two UK Biotechnology and Biological Sciences Research Council Doctoral Training Partnership studentships (to D.M.F. and S.F.), a Tools and Resources Development Fund award (BB/N021703/1, to P.A.E.), Royal Society Research Grants (to P.A.E. and C.E.E.), and North West Cancer Research grants (CR1088 and CR1097, to P.A.E.). Funding for N.K. from the NIH (5RO1GM114409) is also acknowledged.
Glasgow Author(s) Enlighten ID:Keeshan, Dr Karen
Authors: Foulkes, D. M., Byrne, D. P., Yeung, W., Shrestha, S., Bailey, F. P., Ferries, S., Eyers, C. E., Keeshan, K., Wells, C., Drewry, D. H., Zuercher, W. J., Kannan, N., and Eyers, P. A.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Journal Name:Science Signaling
Publisher:American Association for the Advancement of Science
ISSN (Online):1937-9145
Copyright Holders:Copyright © 2018 The Authors
First Published:First published in Science Signaling 11(549):eaat7951
Publisher Policy:Reproduced in accordance with the copyright policy of the publisher

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