Journal article
Selective Inhibition of STAT3 Phosphorylation Using a Nuclear-Targeted Kinase Inhibitor
ACS chemical biology, Vol.12(9), pp.2371-2378
09/15/2017
DOI: 10.1021/acschembio.7b00341
PMCID: PMC5761070
PMID: 28787571
Abstract
The discovery of compounds that selectively modulate signaling and effector proteins downstream of EGFR could have important implications for understanding specific roles for pathway activation. A complicating factor for receptor tyrosine kinases is their capacity to be translocated to the nucleus upon ligand engagement. Once localized in subcellular compartments like the nucleus, the roles for EGFR take on additional features, many of which are still being revealed. Additionally, nuclear localization of EGFR has been implicated in downstream events that have significance for therapy resistance and disease progression. The challenges to addressing the differential roles for EGFR in the nucleus motivated experimental approaches that can selectively modulate its subcellular function. By adding modifications to the established EGFR kinase inhibitor gefitinib, an approach to small molecule conjugates with a unique nuclear-targeting peptoid sequence was tested in both human and murine breast tumor cell models for their capacity to inhibit EGF-stimulated activation of ERK1/2 and STAT3. While gefitinib alone inhibits both of these downstream effectors, data acquired here indicate that compartmentalization of the gefitinib conjugates allows for pathway specific inhibition of STAT3 while not affecting ERK1/2 signaling. The inhibitor conjugates offered a more direct route to evaluate the role of EGF-stimulated epithelial-to-mesenchymal transition in these breast cancer cell models. These conjugates revealed that STAT3 activation is not involved in EGF-induced EMT, and instead utilization of the cytoplasmic MAP kinase signaling pathway is critical to this process. This is the first example of a conjugate kinase inhibitor capable of partitioning to the nucleus and offers a new approach to enhancing kinase inhibitor specificity.
Details
- Title: Subtitle
- Selective Inhibition of STAT3 Phosphorylation Using a Nuclear-Targeted Kinase Inhibitor
- Creators
- Matthew D. Bartolowits - Purdue University West LafayetteWells Brown - Purdue University West LafayetteRemah Ali - Purdue University West LafayetteAnthony M. Pedley - Purdue University West LafayetteQingshou Chen - Purdue University West LafayetteKyle E. Harvey - Purdue University West LafayetteMichael K. Wendt - Purdue University West LafayetteVincent Jo Davisson - Purdue University West Lafayette
- Resource Type
- Journal article
- Publication Details
- ACS chemical biology, Vol.12(9), pp.2371-2378
- DOI
- 10.1021/acschembio.7b00341
- PMID
- 28787571
- PMCID
- PMC5761070
- NLM abbreviation
- ACS Chem Biol
- ISSN
- 1554-8929
- eISSN
- 1554-8937
- Publisher
- Amer Chemical Soc
- Number of pages
- 8
- Grant note
- R00CA166140; R01CA207751 / National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA P30CA023168 / Purdue Center for Cancer Research via a National Institutes of Health NCI Purdue Research Foundation RSG-CSM130259 / American Cancer Society Bilsland Dissertation Fellowship R01CA207751 / NATIONAL CANCER INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) W81XWH-10-0105 / Department of Defense Breast Cancer Research Program; United States Department of Defense Concept Award Phase 1
- Language
- English
- Date published
- 09/15/2017
- Academic Unit
- Biochemistry and Molecular Biology; Internal Medicine
- Record Identifier
- 9984460324402771
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