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Therefore, we hypothesized that analogues of KX2-391 may inhibit oncogenic kinases other than Src. A set of 4-aroylaminophenyl-<jats:italic>N<\/jats:italic>-benzylacetamides were synthesized and found to be more active against leukemia cell lines compared to solid tumor cell lines. <jats:italic>N<\/jats:italic>-(4-(2-(benzylamino)-2-oxoethyl)phenyl)-4-chlorobenzamide (<jats:bold>4e<\/jats:bold>) exhibited activities at IC<jats:sub>50<\/jats:sub> 0.96 \u00b5M, 1.62 \u00b5M, 1.90 \u00b5M and 4.23 \u00b5M against NB4, HL60, MV4-11 and K562 leukemia cell lines, respectively. We found that underlying mechanisms of <jats:bold>4e<\/jats:bold> did not include tubulin polymerization or Src inhibition. Such results interestingly suggested that scaffold-hopping of KX2-391 may change the two main underlying cytotoxic mechanisms (Src and tubulin). Kinase profiling using two methods revealed that <jats:bold>4e<\/jats:bold> significantly reduces the activities of some other potent oncogenic kinases like the MAPK member ERK1\/2 (&amp;gt;99%) and it also greatly upregulates the pro-apoptotic c-Jun kinase (84%). This research also underscores the importance of thorough investigation of total kinase activities as part of the structure-activity relationship studies.<\/jats:p>","DOI":"10.3389\/fonc.2022.879457","type":"journal-article","created":{"date-parts":[[2022,5,20]],"date-time":"2022-05-20T20:44:51Z","timestamp":1653079491000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["SAR Probing of KX2-391 Provided Analogues With Juxtaposed Activity Profile Against Major Oncogenic Kinases"],"prefix":"10.3389","volume":"12","author":[{"given":"Abdelsattar M.","family":"Omar","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maan T.","family":"Khayat","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Farid","family":"Ahmed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yosra 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