{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T11:51:19Z","timestamp":1789645879752,"version":"4.0.0"},"reference-count":44,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2024,6,19]],"date-time":"2024-06-19T00:00:00Z","timestamp":1718755200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health","doi-asserted-by":"publisher","award":["ZIA BC 006538"],"award-info":[{"award-number":["ZIA BC 006538"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health","doi-asserted-by":"publisher","award":["GRK2873 (49483089)"],"award-info":[{"award-number":["GRK2873 (49483089)"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"German Research Foundation","doi-asserted-by":"publisher","award":["ZIA BC 006538"],"award-info":[{"award-number":["ZIA BC 006538"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"German Research Foundation","doi-asserted-by":"publisher","award":["GRK2873 (49483089)"],"award-info":[{"award-number":["GRK2873 (49483089)"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Immunomodulatory imide drugs (IMiDs) play a crucial role in the treatment landscape across various stages of multiple myeloma. Despite their evident efficacy, some patients may exhibit primary resistance to IMiD therapy, and acquired resistance commonly arises over time leading to inevitable relapse. It is critical to develop novel therapeutic options to add to the treatment arsenal to overcome IMiD resistance. We designed, synthesized, and screened a new class of polyfluorinated thalidomide analogs and investigated their anti-cancer, anti-angiogenic, and anti-inflammatory activity using in vitro and ex vivo biological assays. We identified four lead compounds that exhibit potent anti-myeloma, anti-angiogenic, anti-inflammatory properties using three-dimensional tumor spheroid models, in vitro tube formation, and ex vivo human saphenous vein angiogenesis assays, as well as the THP-1 inflammatory assay. Western blot analyses investigating the expression of proteins downstream of cereblon (CRBN) reveal that Gu1215, our primary lead candidate, exerts its activity through a CRBN-independent mechanism. Our findings demonstrate that the lead compound Gu1215 is a promising candidate for further preclinical development to overcome intrinsic and acquired IMiD resistance in multiple myeloma.<\/jats:p>","DOI":"10.3390\/biom14060725","type":"journal-article","created":{"date-parts":[[2024,6,20]],"date-time":"2024-06-20T03:46:29Z","timestamp":1718855189000},"page":"725","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Preclinical Evaluation of a Novel Series of Polyfluorinated Thalidomide Analogs in Drug-Resistant Multiple Myeloma"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9421-8224","authenticated-orcid":false,"given":"Blaire E.","family":"Barton","sequence":"first","affiliation":[{"name":"Molecular Pharmacology Section, Genitourinary Malignancies Branch, Center for Cancer Research, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9305-3560","authenticated-orcid":false,"given":"Matthew K.","family":"Collins","sequence":"additional","affiliation":[{"name":"Molecular Pharmacology Section, Genitourinary Malignancies Branch, Center for Cancer Research, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6928-3833","authenticated-orcid":false,"given":"Cindy H.","family":"Chau","sequence":"additional","affiliation":[{"name":"Molecular Pharmacology Section, Genitourinary Malignancies Branch, Center for Cancer Research, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyoyoung","family":"Choo-Wosoba","sequence":"additional","affiliation":[{"name":"Biostatics and Data Management Section, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8990-158X","authenticated-orcid":false,"given":"David J.","family":"Venzon","sequence":"additional","affiliation":[{"name":"Biostatics and Data Management Section, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5638-1955","authenticated-orcid":false,"given":"Christian","family":"Steinebach","sequence":"additional","affiliation":[{"name":"Pharmaceutical Institute, Pharmaceutical & Medicinal Chemistry, University of Bonn, 53121 Bonn, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4461-1164","authenticated-orcid":false,"given":"Kathleen M.","family":"Garchitorena","sequence":"additional","affiliation":[{"name":"Molecular Pharmacology Section, Genitourinary Malignancies Branch, Center for Cancer Research, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bhruga","family":"Shah","sequence":"additional","affiliation":[{"name":"Inova Heart and Vascular Institute, Inova Health System, Falls Church, VA 22042, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric L.","family":"Sarin","sequence":"additional","affiliation":[{"name":"Inova Heart and Vascular Institute, Inova Health System, Falls Church, VA 22042, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9376-7897","authenticated-orcid":false,"given":"Michael","family":"G\u00fctschow","sequence":"additional","affiliation":[{"name":"Pharmaceutical Institute, Pharmaceutical & Medicinal Chemistry, University of Bonn, 53121 Bonn, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2428-5613","authenticated-orcid":false,"given":"William D.","family":"Figg","sequence":"additional","affiliation":[{"name":"Molecular Pharmacology Section, Genitourinary Malignancies Branch, Center for Cancer Research, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,6,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"12","DOI":"10.3322\/caac.21820","article-title":"Cancer Statistics, 2024","volume":"74","author":"Siegel","year":"2024","journal-title":"CA Cancer J. 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