{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T14:49:07Z","timestamp":1782485347892,"version":"3.54.5"},"reference-count":32,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T00:00:00Z","timestamp":1782432000000},"content-version":"vor","delay-in-days":25,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T00:00:00Z","timestamp":1780272000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Chem Biol Drug Des"],"published-print":{"date-parts":[[2026,6]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Protein kinase C iota (PKC\u03b9) is an atypical PKC isoform overexpressed in several human cancers and associated with tumor initiation, maintenance, and resistance to therapy. Meroxest, a synthetic naphthoquinone merosesquiterpene previously shown to exert antitumor activity in breast cancer models, has an incompletely defined mechanism of action. Here, we profiled meroxest against a 410\u2010kinase panel and synthesized a focused set of analogues to obtain preliminary PKC\u03b9\u2010oriented structure\u2013activity information. At 10\u2009\u03bcM, meroxest reduced PKC\u03b9 enzymatic activity to 52% of control and Cdc7\/cyclin B1 activity to 63%, identifying PKC\u03b9 as the most inhibited kinase in the panel while also indicating that additional kinase targets may contribute to the biological activity of this scaffold. Docking studies supported a plausible interaction of meroxest within the PKC\u03b9 catalytic site, including hydrogen\u2010bond contacts with Gly398 and Phe423 consistent with an ATP\u2010competitive binding mode. Biochemical evaluation of a focused library against PKC\u03b9 at 10\u2009\u03bcM showed that preservation of the quinone framework was important for activity, whereas most structural modifications produced only limited changes under the assay conditions used. Compound\n                    <jats:bold>19<\/jats:bold>\n                    , lacking the methyl substituent on the naphthoquinone ring, showed a modest improvement relative to meroxest. Overall, these results support PKC\u03b9 as a leading candidate target emerging from the meroxest kinase profile and identify compound\n                    <jats:bold>19<\/jats:bold>\n                    as a scaffold for further optimization. Future studies will focus on further optimization to improve the modest PKC\u03b9 inhibitory potency, evaluate activity against Cdc7\/cyclin B1 beyond the parent compound, and validate target engagement in cell\u2010based assays, aiming to identify optimal candidates.\n                  <\/jats:p>","DOI":"10.1111\/cbdd.70348","type":"journal-article","created":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T11:37:08Z","timestamp":1782473828000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Design, Optimization and Mechanistic Insights Into Terpenoid\u2010Derived Inhibitors of Protein Kinase C Iota"],"prefix":"10.1111","volume":"107","author":[{"given":"Rachid","family":"Chahboun","sequence":"first","affiliation":[{"name":"Department of Organic Chemistry, Faculty of Sciences, Institute of Biotechnology University of Granada  Granada Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fernando","family":"Rodr\u00edguez\u2010Serrano","sequence":"additional","affiliation":[{"name":"Biopathology and Regenerative Medicine Institute (IBIMER) University of Granada  Granada Spain"},{"name":"Instituto de Investigaci\u00f3n Biosanitaria de Granada (ibs.GRANADA)  Granada Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u00c1ngel","family":"Bueno","sequence":"additional","affiliation":[{"name":"Department of Organic Chemistry, Faculty of Sciences, Institute of Biotechnology University of Granada  Granada Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nuria","family":"Mut\u2010Salud","sequence":"additional","affiliation":[{"name":"Biopathology and Regenerative Medicine Institute (IBIMER) University of Granada  Granada Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ram\u00f3n","family":"Alvarez\u2010Manzaneda","sequence":"additional","affiliation":[{"name":"Area of Organic Chemistry, Department of Chemistry and Physics University of Almer\u00eda  Almer\u00eda Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Enrique","family":"Alvarez\u2010Manzaneda","sequence":"additional","affiliation":[{"name":"Department of Organic Chemistry, Faculty of Sciences, Institute of Biotechnology University of Granada  Granada Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9816-8482","authenticated-orcid":false,"given":"Antonio","family":"Fern\u00e1ndez","sequence":"additional","affiliation":[{"name":"Department of Organic Chemistry, Faculty of Sciences, Institute of Biotechnology University of Granada  Granada Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,6,26]]},"reference":[{"key":"e_1_2_10_2_1","unstructured":"Broad Institute.2025.\u201cMorpheus.\u201d [Software].https:\/\/software.broadinstitute.org\/morpheus. 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