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treatment of cancer due to its function as an immunoenhancer, but it has limitations in its cytotoxic efficacy. The proteasome inhibitor ixazomib is a landmark drug in the treatment of multiple myeloma with a high anti-cancer activity. Herein, we conjugated the pharmacophore of ubenimex and the boric acid of ixazomib to obtain a dual CD13 and proteasome inhibitor 7 (BC-05). BC-05 exhibited potent inhibitory activity on both human CD13 (IC50 = 0.13 \u03bcM) and the 20S proteasome (IC50 = 1.39 \u03bcM). Although BC-05 displayed lower anti-proliferative activity than that of ixazomib in vitro, an advantage was established in the in vivo anti-cancer efficacy and prolongation of survival time, which may be due to its anti-metastatic and immune-stimulating activity. A pharmacokinetic study revealed that BC-05 is a potentially orally active agent with an F% value of 24.9%. Moreover, BC-05 showed more favorable safety profiles than those of ixazomib in preliminary toxicity studies. Overall, the results indicate that BC-05 is a promising drug candidate for the treatment of multiple myeloma.<\/jats:p>","DOI":"10.3390\/molecules28176343","type":"journal-article","created":{"date-parts":[[2023,8,30]],"date-time":"2023-08-30T10:30:52Z","timestamp":1693391452000},"page":"6343","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Discovery of a Novel Ubenimex Derivative as a First-in-Class Dual CD13\/Proteasome Inhibitor for the Treatment of Cancer"],"prefix":"10.3390","volume":"28","author":[{"given":"Jian","family":"Zhang","sequence":"first","affiliation":[{"name":"College of Pharmacy, Weifang Medical University, Weifang 261053, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Simin","family":"Sun","sequence":"additional","affiliation":[{"name":"Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, 5 Yushan Road, Qingdao 266003, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jinyu","family":"Liu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, 5 Yushan Road, Qingdao 266003, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Liang","family":"Zhang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, 5 Yushan Road, Qingdao 266003, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Di","family":"Guo","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Weifang Medical University, Weifang 261053, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Naixin","family":"Zhang","sequence":"additional","affiliation":[{"name":"Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin 300070, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jun","family":"Zhao","sequence":"additional","affiliation":[{"name":"Marine Biomedical Research Institute of Qingdao, Qingdao 266071, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8064-1435","authenticated-orcid":false,"given":"Dexin","family":"Kong","sequence":"additional","affiliation":[{"name":"Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin 300070, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tongqiang","family":"Xu","sequence":"additional","affiliation":[{"name":"Marine Biomedical Research Institute of Qingdao, Qingdao 266071, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xuejian","family":"Wang","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Weifang Medical University, Weifang 261053, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wenfang","family":"Xu","sequence":"additional","affiliation":[{"name":"Marine Biomedical Research Institute of Qingdao, Qingdao 266071, China"},{"name":"Laboratory for Marine Drugs and Bioproducts, Qingdao National Laboratory for Marine Science and Technology, Qingdao 266237, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3684-2106","authenticated-orcid":false,"given":"Xiaoyang","family":"Li","sequence":"additional","affiliation":[{"name":"Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, 5 Yushan Road, Qingdao 266003, China"},{"name":"Marine Biomedical Research Institute of Qingdao, Qingdao 266071, China"},{"name":"Laboratory for Marine Drugs and Bioproducts, Qingdao National Laboratory for Marine Science and Technology, Qingdao 266237, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6612-4888","authenticated-orcid":false,"given":"Yuqi","family":"Jiang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, 5 Yushan Road, Qingdao 266003, China"},{"name":"Marine Biomedical Research Institute of Qingdao, Qingdao 266071, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,8,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1002\/med.20044","article-title":"Aminopeptidase-n\/cd13 (ec 3.4.11.2) inhibitors: Chemistry, biological evaluations, and therapeutic prospects","volume":"26","author":"Bauvois","year":"2006","journal-title":"Med. 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