Recent discoveries in GPCR signaling have elucidated multiple critical roles of beta-arrestins which are scaffolding proteins that regulate GPCR internalization and signaling. Beta-arrestins are promising to clinical targets, because mice with a knockout of a single beta-arrestin have no overt phenotype, while dual knockout of beta-arrestin1 and beta-arrestin2 is lethal. Also, bladder cancer cells express elevated levels of beta-arrestin2 and one of its activators, the thromboxane-beta GPCR. This increase correlates with a poor clinical prognosis and suggests beta-arrestin2 as a bladder cancer target. Although GPCRs are a major clinical target, to date there are no small molecule regulators for beta-arrestins. Using high performance docking on the NICS Kraken supercomputer, we have conducted virtual screening of a 1.4 million compound library and identified ~250 potential beta-arrestin2 inhibitors. We then created and validated a high throughput and high-content screen targeting GPCR/ B-arrestin2 interactions and tested 61 predicted inhibitory compounds, 15 of which decreased receptor internalization by >40%, validating our discovery strategy. We will complete the screening of all the predicted inhibitors and carry out lead optimization to increase their potency and selectivity for beta-arrestin2. The resulting first selective inhibitors of betaarrestin2 will be used to determine their effect and selectivity on downstream GPCR signaling events in model cell systems. We will also test our beta-arrestin2 inhibitor for anticancer activity using cell based and animal models of bladder cancer. The success of this study will warrant the development of beta-arrestin2 inhibitors as therapeutic agents for bladder cancer and other diseases associated with aberrant betaarrestin- mediated signal transduction.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Exploratory Grants (P20)
Project #
1P20GM109091-01
Application #
8653310
Study Section
Special Emphasis Panel (ZGM1-TWD-A (C1))
Project Start
Project End
Budget Start
2014-07-10
Budget End
2015-04-30
Support Year
1
Fiscal Year
2014
Total Cost
$235,875
Indirect Cost
$11,625
Name
University of South Carolina at Columbia
Department
Type
DUNS #
041387846
City
Columbia
State
SC
Country
United States
Zip Code
29208
Jenkins, Laura M; Singh, Priyanka; Varadaraj, Archana et al. (2016) Altering the Proteoglycan State of Transforming Growth Factor β Type III Receptor (TβRIII)/Betaglycan Modulates Canonical Wnt/β-Catenin Signaling. J Biol Chem 291:25716-25728
Piroli, Gerardo G; Manuel, Allison M; Clapper, Anna C et al. (2016) Succination is Increased on Select Proteins in the Brainstem of the NADH dehydrogenase (ubiquinone) Fe-S protein 4 (Ndufs4) Knockout Mouse, a Model of Leigh Syndrome. Mol Cell Proteomics 15:445-61
Jeong, Ha-Won; Choi, Ran Hee; McClellan, Jamie L et al. (2016) Tribbles 3 inhibits brown adipocyte differentiation and function by suppressing insulin signaling. Biochem Biophys Res Commun 470:783-91
Cheng, Bei; He, Huacheng; Huang, Tao et al. (2016) Gold Nanosphere Gated Mesoporous Silica Nanoparticle Responsive to Near-Infrared Light and Redox Potential as a Theranostic Platform for Cancer Therapy. J Biomed Nanotechnol 12:435-49
Hegde, Shweta; Ji, Hao; Oliver, David et al. (2016) PDE11A regulates social behaviors and is a key mechanism by which social experience sculpts the brain. Neuroscience 335:151-69
He, Huacheng; Altomare, Diego; Ozer, Ufuk et al. (2016) Cancer cell-selective killing polymer/copper combination. Biomater Sci 4:115-20
Rai, R; Zhang, F; Colavita, K et al. (2016) Arginyltransferase suppresses cell tumorigenic potential and inversely correlates with metastases in human cancers. Oncogene 35:4058-68
Kindy, Mark S; Yu, Jin; Zhu, Hong et al. (2016) A therapeutic cancer vaccine against GL261 murine glioma. J Transl Med 14:1
Broude, Eugenia V; Győrffy, Balázs; Chumanevich, Alexander A et al. (2015) Expression of CDK8 and CDK8-interacting Genes as Potential Biomarkers in Breast Cancer. Curr Cancer Drug Targets 15:739-49
Gomez, Adrian M; Altomare, Diego; Sun, Wei-Lun et al. (2015) Prefrontal microRNA-221 Mediates Environmental Enrichment-Induced Increase of Locomotor Sensitivity to Nicotine. Int J Neuropsychopharmacol 19:

Showing the most recent 10 out of 20 publications