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The available BCL6 BTB\u2010specific inhibitors are poorly water soluble, thus, limiting their absorption in vivo and our understanding of therapeutic strategy targeting GC. We synthesized a prodrug (AP\u20104\u2010287) from a potent BCL6 BTB inhibitor (FX1) with improved aqueous solubility and pharmacokinetics (PK) in mice. We also evaluated its in vivo biological activity on humoral immune responses using the sheep red blood cells (SRBC)\u2010vaccination mouse model. AP\u20104\u2010287 had a significant higher aqueous solubility and was readily converted to FX1 in vivo after intraperitoneally (i.p.) administration, but a shorter half\u2010life in vivo. Importantly, AP\u20104\u2010287 treatment led to a reversible effect on (1) the reduction in the frequency of splenic Ki67\n                    <jats:sup>+<\/jats:sup>\n                    CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cells, Tfh cells, and GC B cells; (2) lower GC formation following vaccination; and (3) a decrease in the titers of antigen\u2010specific IgG and IgM antibodies. Our study advances the preclinical development of drug targeting BCL6 BTB domain for the treatment of diseases that are associated with abnormal BCL6 elevation.\n                  <\/jats:p>","DOI":"10.1002\/eji.202049150","type":"journal-article","created":{"date-parts":[[2021,7,21]],"date-time":"2021-07-21T03:59:52Z","timestamp":1626839992000},"page":"2441-2451","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["BCL6 BTB\u2010specific inhibitor reversely represses T\u2010cell activation, Tfh cells differentiation, and germinal center reaction in vivo"],"prefix":"10.1002","volume":"51","author":[{"given":"Yanhui","family":"CAI","sequence":"first","affiliation":[{"name":"The Wistar Institute  Philadelphia PA USA"},{"name":"Gilead Sciences, Inc.  333 Lakeside Dr Foster City CA 94404"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adi Narayana Reddy","family":"Poli","sequence":"additional","affiliation":[{"name":"The Wistar Institute  Philadelphia PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Surya","family":"Vadrevu","sequence":"additional","affiliation":[{"name":"The Wistar Institute  Philadelphia PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kwasi","family":"Gyampoh","sequence":"additional","affiliation":[{"name":"The Wistar Institute  Philadelphia PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Colin","family":"Hart","sequence":"additional","affiliation":[{"name":"The Wistar Institute  Philadelphia PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian","family":"Ross","sequence":"additional","affiliation":[{"name":"The Wistar Institute  Philadelphia PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matt","family":"Fair","sequence":"additional","affiliation":[{"name":"The Wistar Institute  Philadelphia PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fengtian","family":"Xue","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences University of Maryland School of Pharmacy  Baltimore MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph M.","family":"Salvino","sequence":"additional","affiliation":[{"name":"The Wistar Institute  Philadelphia PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luis J.","family":"Montaner","sequence":"additional","affiliation":[{"name":"The Wistar Institute  Philadelphia PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,9,16]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-17-1444"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M803490200"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2009-06-227017"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2011.03.025"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1176676"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1175870"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2005.03.037"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1080\/10428190290033305"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-16-2071"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V83.7.1757.1757"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2002-11-3387"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1586\/17474086.2013.826928"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.3892\/ol.2016.4313"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI85795"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2016.07.006"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1111\/jmp.12438"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2017.08.081"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrd2468"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tips.2016.11.008"},{"key":"e_1_2_9_21_1","first-page":"19","article-title":"Amino acid transporters and glutamine metabolism in breast cancer","author":"Cha Y. 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