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Genetic variations of ABCB4 are associated with rare cholestatic liver diseases, the most severe being progressive familial intrahepatic cholestasis type 3, for which most of patients require liver transplantation before adulthood. Therefore, the development of alternative pharmacotherapies is urgently needed. We have previously shown that structural analogues of roscovitine rescue the maturation, localisation and indirectly the function of class II intracellularly-retained ABCB4 variants. Nevertheless, in order to develop molecules with better benefit\/toxicity ratios, new structural analogues of roscovitine were tested in cell models as potential correctors of three class II ABCB4 variants. We show here that nine roscovitine analogues are able to significantly rescue the maturation and canalicular localisation of these ABCB4 variants. Three of these analogues were also able to partially restore the transporter-mediated activity of ABCB4 variants, while being less inhibitory of wild type ABCB4 function than roscovitine itself. In addition, ensemble docking calculations suggest that the selected roscovitine analogues may directly interact with wild type or mutated ABCB4. Our results represent a new step towards the identification of pharmacological correctors for ER-retained variants of the ABCB4 transporter.<\/jats:p>","DOI":"10.1038\/s41598-026-39840-6","type":"journal-article","created":{"date-parts":[[2026,2,25]],"date-time":"2026-02-25T02:04:57Z","timestamp":1771985097000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Molecular characterisation of the trafficking rescue of defective ABCB4 variants by roscovitine analogues"],"prefix":"10.1038","volume":"16","author":[{"given":"Manon","family":"Banet","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Veronica","family":"Crespi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jonathan","family":"Elie","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yosra","family":"Riahi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mounia","family":"Lakli","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elodie","family":"Mareux","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emmanuel","family":"Gonzales","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emmanuel","family":"Jacquemin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laurent","family":"Meijer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Martine","family":"Lapalus","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Florent","family":"Di Meo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas","family":"Falgui\u00e8res","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2026,2,25]]},"reference":[{"key":"39840_CR1","doi-asserted-by":"publisher","first-page":"1162","DOI":"10.1002\/humu.24418","volume":"43","author":"M Dean","year":"2022","unstructured":"Dean, M., Moitra, K. & Allikmets, R. 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