{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T10:35:19Z","timestamp":1772966119756,"version":"3.50.1"},"reference-count":52,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2022,7,19]],"date-time":"2022-07-19T00:00:00Z","timestamp":1658188800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia (FCT)","award":["PTDC\/EEI-ESS\/4923\/2014"],"award-info":[{"award-number":["PTDC\/EEI-ESS\/4923\/2014"]}]},{"name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia (FCT)","award":["SFRH\/BD\/111654\/2015"],"award-info":[{"award-number":["SFRH\/BD\/111654\/2015"]}]},{"name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia (FCT)","award":["UIDB\/04138\/2020"],"award-info":[{"award-number":["UIDB\/04138\/2020"]}]},{"name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia (FCT)","award":["UIDP\/04138\/2020"],"award-info":[{"award-number":["UIDP\/04138\/2020"]}]},{"name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia (FCT)","award":["UID\/CEC\/00408\/2019"],"award-info":[{"award-number":["UID\/CEC\/00408\/2019"]}]},{"name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia (FCT)","award":["LISBOA-01-0145-FEDER-402-022125"],"award-info":[{"award-number":["LISBOA-01-0145-FEDER-402-022125"]}]},{"name":"Strategic Projects","award":["PTDC\/EEI-ESS\/4923\/2014"],"award-info":[{"award-number":["PTDC\/EEI-ESS\/4923\/2014"]}]},{"name":"Strategic Projects","award":["SFRH\/BD\/111654\/2015"],"award-info":[{"award-number":["SFRH\/BD\/111654\/2015"]}]},{"name":"Strategic Projects","award":["UIDB\/04138\/2020"],"award-info":[{"award-number":["UIDB\/04138\/2020"]}]},{"name":"Strategic Projects","award":["UIDP\/04138\/2020"],"award-info":[{"award-number":["UIDP\/04138\/2020"]}]},{"name":"Strategic Projects","award":["UID\/CEC\/00408\/2019"],"award-info":[{"award-number":["UID\/CEC\/00408\/2019"]}]},{"name":"Strategic Projects","award":["LISBOA-01-0145-FEDER-402-022125"],"award-info":[{"award-number":["LISBOA-01-0145-FEDER-402-022125"]}]},{"name":"Portuguese Mass Spectrometry Network","award":["PTDC\/EEI-ESS\/4923\/2014"],"award-info":[{"award-number":["PTDC\/EEI-ESS\/4923\/2014"]}]},{"name":"Portuguese Mass Spectrometry Network","award":["SFRH\/BD\/111654\/2015"],"award-info":[{"award-number":["SFRH\/BD\/111654\/2015"]}]},{"name":"Portuguese Mass Spectrometry Network","award":["UIDB\/04138\/2020"],"award-info":[{"award-number":["UIDB\/04138\/2020"]}]},{"name":"Portuguese Mass Spectrometry Network","award":["UIDP\/04138\/2020"],"award-info":[{"award-number":["UIDP\/04138\/2020"]}]},{"name":"Portuguese Mass Spectrometry Network","award":["UID\/CEC\/00408\/2019"],"award-info":[{"award-number":["UID\/CEC\/00408\/2019"]}]},{"name":"Portuguese Mass Spectrometry Network","award":["LISBOA-01-0145-FEDER-402-022125"],"award-info":[{"award-number":["LISBOA-01-0145-FEDER-402-022125"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>The epidermal growth factor receptor (EGFR) is upregulated in glioblastoma, becoming an attractive therapeutic target. However, activation of compensatory pathways generates inputs to downstream PI3Kp110\u03b2 signaling, leading to anti-EGFR therapeutic resistance. Moreover, the blood\u2013brain barrier (BBB) limits drugs\u2019 brain penetration. We aimed to discover EGFR\/PI3Kp110\u03b2 pathway inhibitors for a multi-targeting approach, with favorable ADMET and BBB-permeant properties. We used quantitative structure\u2013activity relationship models and structure-based virtual screening, and assessed ADMET properties, to identify BBB-permeant drug candidates. Predictions were validated in in vitro models of the human BBB and BBB-glioma co-cultures. The results disclosed 27 molecules (18 EGFR, 6 PI3Kp110\u03b2, and 3 dual inhibitors) for biological validation, performed in two glioblastoma cell lines (U87MG and U87MG overexpressing EGFR). Six molecules (two EGFR, two PI3Kp110\u03b2, and two dual inhibitors) decreased cell viability by 40\u201399%, with the greatest effect observed for the dual inhibitors. The glioma cytotoxicity was confirmed by analysis of targets\u2019 downregulation and increased apoptosis (15\u201385%). Safety to BBB endothelial cells was confirmed for three of those molecules (one EGFR and two PI3Kp110\u03b2 inhibitors). These molecules crossed the endothelial monolayer in the BBB in vitro model and in the BBB-glioblastoma co-culture system. These results revealed novel drug candidates for glioblastoma treatment.<\/jats:p>","DOI":"10.3390\/cancers14143506","type":"journal-article","created":{"date-parts":[[2022,7,19]],"date-time":"2022-07-19T23:10:22Z","timestamp":1658272222000},"page":"3506","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Multi-Targeting Approach in Glioblastoma Using Computer-Assisted Drug Discovery Tools to Overcome the Blood\u2013Brain Barrier and Target EGFR\/PI3Kp110\u03b2 Signaling"],"prefix":"10.3390","volume":"14","author":[{"given":"Catarina","family":"Franco","sequence":"first","affiliation":[{"name":"LASIGE, Department of Informatics, Faculty of Sciences, Universidade de Lisboa, Campo Grande, 1749-016 Lisboa, Portugal"},{"name":"Research Institute for Medicines, Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5207-7136","authenticated-orcid":false,"given":"Samina","family":"Kausar","sequence":"additional","affiliation":[{"name":"LASIGE, Department of Informatics, Faculty of Sciences, Universidade de Lisboa, Campo Grande, 1749-016 Lisboa, Portugal"},{"name":"Research Institute for Medicines, Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6552-1822","authenticated-orcid":false,"given":"Margarida F. B.","family":"Silva","sequence":"additional","affiliation":[{"name":"Research Institute for Medicines, Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal"},{"name":"Department of Pharmaceutical Sciences and Medicines, Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5790-9181","authenticated-orcid":false,"given":"Rita C.","family":"Guedes","sequence":"additional","affiliation":[{"name":"Research Institute for Medicines, Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal"},{"name":"Department of Pharmaceutical Sciences and Medicines, Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3588-8746","authenticated-orcid":false,"given":"Andre O.","family":"Falcao","sequence":"additional","affiliation":[{"name":"LASIGE, Department of Informatics, Faculty of Sciences, Universidade de Lisboa, Campo Grande, 1749-016 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8493-4649","authenticated-orcid":false,"given":"Maria Alexandra","family":"Brito","sequence":"additional","affiliation":[{"name":"Research Institute for Medicines, Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal"},{"name":"Department of Pharmaceutical Sciences and Medicines, Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2022,7,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1878","DOI":"10.2174\/0929867326666190201113004","article-title":"Thioredoxin, glutathione and related molecules in tumors of the nervous system","volume":"27","author":"Branco","year":"2020","journal-title":"Curr. Med. 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