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Yet, the poor understanding of isozymes-specific functions and the limited availability of selective pharmacological modulators of PKC isozymes have limited the clinical translation of PKC-targeting agents. Here, we report the first small-molecule PKC\u03b4-selective activator, the 7<jats:italic>\u03b1<\/jats:italic>-acetoxy-6<jats:italic>\u03b2<\/jats:italic>-benzoyloxy-12-<jats:italic>O<\/jats:italic>-benzoylroyleanone (Roy-Bz), which binds to the PKC\u03b4-C1-domain. Roy-Bz potently inhibited the proliferation of colon cancer cells by inducing a PKC\u03b4-dependent mitochondrial apoptotic pathway involving caspase-3 activation. In HCT116 colon cancer cells, Roy-Bz specifically triggered the translocation of PKC\u03b4 but not other phorbol ester responsive PKCs. Roy-Bz caused a marked inhibition in migration of HCT116 cells in a PKC\u03b4-dependent manner. Additionally, the impairment of colonosphere growth and formation, associated with depletion of stemness markers, indicate that Roy-Bz also targets drug-resistant cancer stem cells, preventing tumor dissemination and recurrence. Notably, in xenograft mouse models, Roy-Bz showed a PKC\u03b4-dependent antitumor effect, through anti-proliferative, pro-apoptotic, and anti-angiogenic activities. Besides, Roy-Bz was non-genotoxic, and in vivo it had no apparent toxic side effects. Collectively, our findings reveal a novel promising anticancer drug candidate. Most importantly, Roy-Bz opens the way to a new era on PKC biology and pharmacology, contributing to the potential redefinition of the structural requirements of isozyme-selective agents, and to the re-establishment of PKC isozymes as feasible therapeutic targets in human diseases.<\/jats:p>","DOI":"10.1038\/s41419-017-0154-9","type":"journal-article","created":{"date-parts":[[2018,1,18]],"date-time":"2018-01-18T11:37:04Z","timestamp":1516275424000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["Discovery of a small-molecule protein kinase C\u03b4-selective activator with promising application in colon cancer therapy"],"prefix":"10.1038","volume":"9","author":[{"given":"Cl\u00e1udia","family":"Bessa","sequence":"first","affiliation":[]},{"given":"Joana","family":"Soares","sequence":"additional","affiliation":[]},{"given":"Liliana","family":"Raimundo","sequence":"additional","affiliation":[]},{"given":"Joana B.","family":"Loureiro","sequence":"additional","affiliation":[]},{"given":"C\u00e9lia","family":"Gomes","sequence":"additional","affiliation":[]},{"given":"Fl\u00e1vio","family":"Reis","sequence":"additional","affiliation":[]},{"given":"Miguel L.","family":"Soares","sequence":"additional","affiliation":[]},{"given":"Daniel","family":"Santos","sequence":"additional","affiliation":[]},{"given":"Chetna","family":"Dureja","sequence":"additional","affiliation":[]},{"given":"Saumya R.","family":"Chaudhuri","sequence":"additional","affiliation":[]},{"given":"Cynthia","family":"Lopez-Haber","sequence":"additional","affiliation":[]},{"given":"Marcelo G.","family":"Kazanietz","sequence":"additional","affiliation":[]},{"given":"Jorge","family":"Gon\u00e7alves","sequence":"additional","affiliation":[]},{"given":"Maria F.","family":"Sim\u00f5es","sequence":"additional","affiliation":[]},{"given":"Patr\u00edcia","family":"Rijo","sequence":"additional","affiliation":[]},{"given":"Luc\u00edlia","family":"Saraiva","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2018,1,18]]},"reference":[{"key":"154_CR1","doi-asserted-by":"publisher","first-page":"937","DOI":"10.1038\/nrd3871","volume":"11","author":"D Mochly-Rosen","year":"2012","unstructured":"Mochly-Rosen, D., Das, K. & Grimes, K. 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