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dc.contributor.authorLan, Lan
dc.contributor.authorLiu, Jiajun
dc.contributor.authorXing, Minli
dc.contributor.authorSmith, Amber R.
dc.contributor.authorWang, Jinan
dc.contributor.authorWu, Xiaoqing
dc.contributor.authorAppelman, Carl
dc.contributor.authorLi, Ke
dc.contributor.authorRoy, Anuradha
dc.contributor.authorGowthaman, Ragul
dc.contributor.authorKaranicolas, John
dc.contributor.authorSomoza, Amber D.
dc.contributor.authorWang, Clay C. C.
dc.contributor.authorMiao, Yinglong
dc.contributor.authorGuzman, Roberto De
dc.contributor.authorOakley, Berl R.
dc.contributor.authorNeufeld, Kristi L.
dc.contributor.authorXu, Liang
dc.identifier.citationLan, L., Liu, J., Xing, M., Smith, A. R., Wang, J., Wu, X., Appelman, C., Li, K., Roy, A., Gowthaman, R., Karanicolas, J., Somoza, A. D., Wang, C., Miao, Y., De Guzman, R., Oakley, B. R., Neufeld, K. L., & Xu, L. (2020). Identification and Validation of an Aspergillus nidulans Secondary Metabolite Derivative as an Inhibitor of the Musashi-RNA Interaction. Cancers, 12(8), 2221.
dc.descriptionThis work is licensed under a Creative Commons Attribution 4.0 International License.en_US
dc.description.abstractRNA-binding protein Musashi-1 (MSI1) is a key regulator of several stem cell populations. MSI1 is involved in tumor proliferation and maintenance, and it regulates target mRNAs at the translational level. The known mRNA targets of MSI1 include Numb, APC, and P21WAF-1, key regulators of Notch/Wnt signaling and cell cycle progression, respectively. In this study, we aim to identify small molecule inhibitors of MSI1–mRNA interactions, which could block the growth of cancer cells with high levels of MSI1. Using a fluorescence polarization (FP) assay, we screened small molecules from several chemical libraries for those that disrupt the binding of MSI1 to its consensus RNA. One cluster of hit compounds is the derivatives of secondary metabolites from Aspergillus nidulans. One of the top hits, Aza-9, from this cluster was further validated by surface plasmon resonance and nuclear magnetic resonance spectroscopy, which demonstrated that Aza-9 binds directly to MSI1, and the binding is at the RNA binding pocket. We also show that Aza-9 binds to Musashi-2 (MSI2) as well. To test whether Aza-9 has anti-cancer potential, we used liposomes to facilitate Aza-9 cellular uptake. Aza-9-liposome inhibits proliferation, induces apoptosis and autophagy, and down-regulates Notch and Wnt signaling in colon cancer cell lines. In conclusion, we identified a series of potential lead compounds for inhibiting MSI1/2 function, while establishing a framework for identifying small molecule inhibitors of RNA binding proteins using FP-based screening methodology.en_US
dc.description.sponsorshipNIH R01 CA178831en_US
dc.description.sponsorshipNIH CA191785en_US
dc.description.sponsorshipNational Institute of General Medical Science (P01GM084077)en_US
dc.description.sponsorshipUniversity of Kansas Bold Aspiration Strategic Initiative Awarden_US
dc.description.sponsorshipNational Cancer Institute Cancer Center Support Grant P30 CA168524en_US
dc.description.sponsorshipKansas Bioscience Authority Rising Star Awarden_US
dc.description.sponsorshipNIH AI074856en_US
dc.description.sponsorshipNIH COBREen_US
dc.description.sponsorshipIrving S. Johnson Fund of the University of Kansas Endowmenten_US
dc.rights© 2020 by the authors. Licensee MDPI, Basel, Switzerland.en_US
dc.subjectRNA-binding proteinsen_US
dc.subjectDrug discoveryen_US
dc.subjectNotch signalingen_US
dc.subjectWnt signalingen_US
dc.subjectCancer therapyen_US
dc.subjectFungi secondary metabolite derivativeen_US
dc.titleIdentification and Validation of an Aspergillus nidulans Secondary Metabolite Derivative as an Inhibitor of the Musashi-RNA Interactionen_US
kusw.kuauthorLan, Lan
kusw.kuauthorLiu, Jiajun
kusw.kuauthorXing, Minli
kusw.kuauthorSmith, Amber R.
kusw.kuauthorWang, Jinan
kusw.kuauthorWu, Xiaoqing
kusw.kuauthorAppelman, Carl
kusw.kuauthorLi, Ke
kusw.kuauthorRoy, Anuradha
kusw.kuauthorGowthaman, Ragul
kusw.kuauthorMiao, Yinglong
kusw.kuauthorGuzman, Roberto De
kusw.kuauthorOakley, Berl R.
kusw.kuauthorNeufeld, Kristi L.
kusw.kuauthorXu, Liang
kusw.kudepartmentMolecular Biosciencesen_US
kusw.kudepartmentBio-NMR Core Facilityen_US
kusw.kudepartmentCenter for Computational Biologyen_US
kusw.kudepartmentHigh Throughput Screening Laboratoryen_US
kusw.oaversionScholarly/refereed, publisher versionen_US
kusw.oapolicyThis item meets KU Open Access policy criteria.en_US

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© 2020 by the authors. Licensee MDPI, Basel, Switzerland.
Except where otherwise noted, this item's license is described as: © 2020 by the authors. Licensee MDPI, Basel, Switzerland.