Please use this identifier to cite or link to this item: http://hdl.handle.net/10397/82134
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dc.contributorDepartment of Applied Biology and Chemical Technologyen_US
dc.creatorYang, Yen_US
dc.creatorVankayalapati, Hen_US
dc.creatorTang, Men_US
dc.creatorZheng, Yen_US
dc.creatorLi, Yen_US
dc.creatorMa, Cen_US
dc.creatorLai, Ken_US
dc.date.accessioned2020-05-05T05:58:48Z-
dc.date.available2020-05-05T05:58:48Z-
dc.identifier.issn1420-3049en_US
dc.identifier.urihttp://hdl.handle.net/10397/82134-
dc.language.isoenen_US
dc.publisherMolecular Diversity Preservation International (MDPI)en_US
dc.rights© 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).en_US
dc.rightsThe following publication Yang Y, Vankayalapati H, Tang M, Zheng Y, Li Y, Ma C, Lai K. Discovery of Novel Inhibitors Targeting Multi-UDP-hexose Pyrophosphorylases as Anticancer Agents. Molecules. 2020; 25(3):645, is available at https://doi.org/10.3390/molecules25030645en_US
dc.subjectCancer metabolismen_US
dc.subjectFragment-based screeningen_US
dc.subjectGalactose-1 phosphate uridylyltransferase (GALT)en_US
dc.subjectGlycosylationen_US
dc.subjectMulti-target approachen_US
dc.subjectPolypharmacologyen_US
dc.subjectUDP-glucose pyrophosphorylase (UGP2)en_US
dc.subjectUDP-hexose pyrophosphorylaseen_US
dc.subjectUDP-N-acetylglucosamine pyrophosphorylase (AGX1/UAP1)en_US
dc.titleDiscovery of novel inhibitors targeting multi-UDP-hexose pyrophosphorylases as anticancer agentsen_US
dc.typeJournal/Magazine Articleen_US
dc.identifier.volume25en_US
dc.identifier.issue3en_US
dc.identifier.doi10.3390/molecules25030645en_US
dcterms.abstractTo minimize treatment toxicities, recent anti-cancer research efforts have switched from broad-based chemotherapy to targeted therapy, and emerging data show that altered cellular metabolism in cancerous cells can be exploited as new venues for targeted intervention. In this study, we focused on, among the altered metabolic processes in cancerous cells, altered glycosylation due to its documented roles in cancer tumorigenesis, metastasis and drug resistance. We hypothesize that the enzymes required for the biosynthesis of UDP-hexoses, glycosyl donors for glycan synthesis, could serve as therapeutic targets for cancers. Through structure-based virtual screening and kinetic assay, we identified a drug-like chemical fragment, GAL-012, that inhibit a small family of UDP-hexose pyrophosphorylases-galactose pyro-phosphorylase (GALT), UDP-glucose pyrophosphorylase (UGP2) and UDP-N-acetylglucosamine pyrophosphorylase (AGX1/UAP1) with an IC50 of 30 µM. The computational docking studies supported the interaction of GAL-012 to the binding sites of GALT at Trp190 and Ser192, UGP2 at Gly116 and Lys127, and AGX1/UAP1 at Asn327 and Lys407, respectively. One of GAL-012 derivatives GAL-012-2 also demonstrated the inhibitory activity against GALT and UGP2. Moreover, we showed that GAL-012 suppressed the growth of PC3 cells in a dose-dependent manner with an EC50 of 75 µM with no effects on normal skin fibroblasts at 200 µM. Western blot analysis revealed reduced expression of pAKT (Ser473), pAKT (Thr308) by 77% and 72%, respectively in the treated cells. siRNA experiments against the respective genes encoding the pyrophosphorylases were also performed and the results further validated the proposed roles in cancer growth inhibition. Finally, synergistic relationships between GAL-012 and tunicamycin, as well as bortezomib (BTZ) in killing cultured cancer cells were observed, respectively. With its unique scaffold and relatively small size, GAL-012 serves as a promising early chemotype for optimization to become a safe, effective, multi-target anti-cancer drug candidate which could be used alone or in combination with known therapeutics.en_US
dcterms.accessRightsopen accessen_US
dcterms.bibliographicCitationMolecules, 3 Feb. 2020, v. 25, no. 3, 645en_US
dcterms.isPartOfMoleculesen_US
dcterms.issued2020-02-03-
dc.identifier.isiWOS:000515384800215-
dc.identifier.scopus2-s2.0-85078878825-
dc.identifier.pmid32028604-
dc.identifier.artn645en_US
dc.description.validate202006 bcmaen_US
dc.description.oaVersion of Recorden_US
dc.identifier.FolderNumbera0615-n06, OA_Scopus/WOSen_US
dc.identifier.SubFormID605-
dc.description.fundingSourceSelf-fundeden_US
dc.description.pubStatusPublisheden_US
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