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The most potent derivative, compound\n                    <jats:bold>5e<\/jats:bold>\n                    bearing a 3,4,5\u2010trimethoxyphenyl chalcone moiety, showed the most effective growth inhibition value against the panel of NCI 60 human cancer cell lines. Thus, it was selected for further investigation for NCI 5\u2009log doses. Interestingly, this trimethoxy\u2010substituted analog inhibited the proliferation of Roswell Park Memorial Institute (RPMI)\u20108226 cells by 96%, at 10\u2009\u00b5M with IC\n                    <jats:sub>50<\/jats:sub>\n                    \u2009=\u20099.09\u2009\u00b1\u20090.34\u2009\u00b5M and selectivity index\u2009=\u20097.19 against normal blood cells. To confirm the selectivity of this compound, it was evaluated against a panel of tyrosine kinase enzymes. Mechanistically, it successfully and selectively inhibited HDAC6, HDAC8, and EGFR with IC\n                    <jats:sub>50<\/jats:sub>\n                    \u2009=\u20090.41\u2009\u00b1\u20090.015, 0.61\u2009\u00b1\u20090.027, and 0.09\u2009\u00b1\u20090.004\u2009\u00b5M, respectively. Furthermore, the selected derivative induced apoptosis via the mitochondrial apoptotic pathway by raising the Bax\/Bcl\u20102 ratio and activating caspases 3, 7, and 9. Also, the flow cytometry analysis of RPMI\u20108226 cells showed that the trimethoxy\u2010substituted analog produced cell cycle arrest in the G1 and S phases at 55.82%. Finally, an in silico study was performed to explore the binding interaction of the most active compound within the zinc\u2010containing binding site of HDAC6 and HDAC8.\n                  <\/jats:p>","DOI":"10.1002\/ardp.202300626","type":"journal-article","created":{"date-parts":[[2024,2,1]],"date-time":"2024-02-01T01:30:20Z","timestamp":1706751020000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Quinazoline\u2010chalcone hybrids as HDAC\/EGFR dual inhibitors: Design, synthesis, mechanistic, and in\u2010silico studies of potential anticancer activity against multiple myeloma"],"prefix":"10.1002","volume":"357","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0179-8398","authenticated-orcid":false,"given":"Mostafa A.","family":"Mansour","sequence":"first","affiliation":[{"name":"Pharmaceutical Chemistry Department, Faculty of Pharmacy Nahda University in Beni\u2010Suef (NUB) Beni\u2010Suef Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4243-9401","authenticated-orcid":false,"given":"Asmaa M.","family":"AboulMagd","sequence":"additional","affiliation":[{"name":"Pharmaceutical Chemistry Department, Faculty of Pharmacy Nahda University in Beni\u2010Suef (NUB) Beni\u2010Suef Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9586-2644","authenticated-orcid":false,"given":"Samar H.","family":"Abbas","sequence":"additional","affiliation":[{"name":"Medicinal Chemistry Department, Faculty of Pharmacy Minia University Minia Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1396-8662","authenticated-orcid":false,"given":"Mohamed","family":"Abdel\u2010Aziz","sequence":"additional","affiliation":[{"name":"Medicinal Chemistry Department, Faculty of Pharmacy Minia University Minia Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hamdy M.","family":"Abdel\u2010Rahman","sequence":"additional","affiliation":[{"name":"Medicinal Chemistry Department, Faculty of Pharmacy Assiut University Assiut Egypt"},{"name":"Pharmaceutical Chemistry Department, Faculty of Pharmacy Badr University in Assiut (BUA) Assiut Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,1,31]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/jbt.23067"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41375-022-01613-1"},{"key":"e_1_2_7_4_1","first-page":"80","volume":"28","author":"Luo X.","year":"2022","journal-title":"Altern. 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