{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T05:30:36Z","timestamp":1786339836310,"version":"build-2736575974"},"reference-count":47,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2026,3,20]],"date-time":"2026-03-20T00:00:00Z","timestamp":1773964800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,3,20]],"date-time":"2026-03-20T00:00:00Z","timestamp":1773964800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100004431","name":"Fondation de France","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004431","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001665","name":"Agence Nationale de la Recherche","doi-asserted-by":"publisher","award":["ANR0005"],"award-info":[{"award-number":["ANR0005"]}],"id":[{"id":"10.13039\/501100001665","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2026,6]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background and purpose<\/jats:title>\n                    <jats:p>\n                      Anthracycline\u2010induced cardiotoxicity, particularly from doxorubicin, remains a major limitation in cancer therapy, contributing to heart failure and long\u2010term morbidity. Prokineticin receptor\u20101 (PKR\n                      <jats:sub>1<\/jats:sub>\n                      ), involved in cardiomyocyte survival and anti\u2010fibrotic signalling, represents a promising therapeutic target. This study evaluated the cardioprotective potential of IS39, a novel non\u2010peptide PKR\n                      <jats:sub>1<\/jats:sub>\n                      agonist, in models of doxorubicin\u2010induced cardiac injury.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Experimental approach<\/jats:title>\n                    <jats:p>\n                      In silico ADME\u2013toxicity profiling, scaffold optimisation and molecular docking were used to refine non\u2010peptide PKR\n                      <jats:sub>1<\/jats:sub>\n                      agonists, replacing the dehydroamide moiety of first\u2010generation compounds with a D\u2010aminoacyl group to enhance metabolic stability. The lead compound IS39 was evaluated\n                      <jats:italic>in vitro<\/jats:italic>\n                      in primary cardiomyocytes and\n                      <jats:italic>in vivo<\/jats:italic>\n                      in a murine model of doxorubicin\u2010induced cardiotoxicity. Parallel studies assessed potential interference with doxorubicin antitumour activity in breast cancer cell lines and 3D tumour spheroids. Endpoints included cardiomyocyte viability, oxidative stress, fibrotic markers, cardiac function, histopathology and systemic tolerability.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key results<\/jats:title>\n                    <jats:p>\n                      IS39 selectively activated PKR\n                      <jats:sub>1<\/jats:sub>\n                      , reduced reactive oxygen species, suppressed profibrotic gene expression and protected cardiomyocytes from doxorubicin\u2010induced cytotoxicity in vitro. These effects were abolished by PKR\n                      <jats:sub>1<\/jats:sub>\n                      knockdown or antagonism, confirming on\u2010target activity, and IS39 did not impair doxorubicin antitumour efficacy. In vivo, IS39 preserved left ventricular ejection fraction, attenuated myocardial fibrosis and apoptosis, and improved cardiac morphology. However, systemic IS39 administration exacerbated doxorubicin\u2010associated weight loss and did not improve overall survival.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions and implications<\/jats:title>\n                    <jats:p>IS39 confers cardioprotection via PKR1\u2010mediated antioxidant and antifibrotic mechanisms. Despite systemic tolerability limitations, these findings support PKR1 as a therapeutic target and justify development of tissue\u2010selective PKR1 agonists for cardio\u2010oncology applications.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/bph.70394","type":"journal-article","created":{"date-parts":[[2026,3,20]],"date-time":"2026-03-20T13:56:54Z","timestamp":1774015014000},"page":"3377-3394","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Second\u2010generation prokineticin PKR\n                    <sub>1<\/sub>\n                    receptor agonists: Advancing cardioprotection against chemotherapy\u2010induced toxicity"],"prefix":"10.1111","volume":"183","author":[{"given":"Anais","family":"Audebrand","sequence":"first","affiliation":[{"name":"INSERM, Regenerative Nanomedicine Laboratory (UMR1260), Faculty of Medicine, FMTS University of Strasbourg  Strasbourg France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9375-6242","authenticated-orcid":false,"given":"Simone","family":"Brogi","sequence":"additional","affiliation":[{"name":"Department of Pharmacy University of Pisa  Pisa Italy"},{"name":"Department of Biotechnology, Chemistry and Pharmacy University of Siena  Siena Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mustafa","family":"Tezeren","sequence":"additional","affiliation":[{"name":"INSERM, Regenerative Nanomedicine Laboratory (UMR1260), Faculty of Medicine, FMTS University of Strasbourg  Strasbourg France"},{"name":"Ulkar Kimya, G.O.P. 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