{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,28]],"date-time":"2026-02-28T04:26:30Z","timestamp":1772252790476,"version":"3.50.1"},"reference-count":86,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2022,6,16]],"date-time":"2022-06-16T00:00:00Z","timestamp":1655337600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"University of Nebraska Medical Center"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>B-cell chronic lymphocytic leukemia (CLL) results from intrinsic genetic defects and complex microenvironment stimuli that fuel CLL cell growth through an array of survival signaling pathways. Novel small-molecule agents targeting the B-cell receptor pathway and anti-apoptotic proteins alone or in combination have revolutionized the management of CLL, yet combination therapy carries significant toxicity and CLL remains incurable due to residual disease and relapse. Single-molecule inhibitors that can target multiple disease-driving factors are thus an attractive approach to combat both drug resistance and combination-therapy-related toxicities. We demonstrate that SRX3305, a novel small-molecule BTK\/PI3K\/BRD4 inhibitor that targets three distinctive facets of CLL biology, attenuates CLL cell proliferation and promotes apoptosis in a dose-dependent fashion. SRX3305 also inhibits the activation-induced proliferation of primary CLL cells in vitro and effectively blocks microenvironment-mediated survival signals, including stromal cell contact. Furthermore, SRX3305 blocks CLL cell migration toward CXCL-12 and CXCL-13, which are major chemokines involved in CLL cell homing and retention in microenvironment niches. Importantly, SRX3305 maintains its anti-tumor effects in ibrutinib-resistant CLL cells. Collectively, this study establishes the preclinical efficacy of SRX3305 in CLL, providing significant rationale for its development as a therapeutic agent for CLL and related disorders.<\/jats:p>","DOI":"10.3390\/ijms23126712","type":"journal-article","created":{"date-parts":[[2022,6,17]],"date-time":"2022-06-17T01:48:12Z","timestamp":1655430492000},"page":"6712","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["A Novel Triple-Action Inhibitor Targeting B-Cell Receptor Signaling and BRD4 Demonstrates Preclinical Activity in Chronic Lymphocytic Leukemia"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5096-5351","authenticated-orcid":false,"given":"Audrey L.","family":"Smith","sequence":"first","affiliation":[{"name":"Eppley Institute for Research in Cancer and Allied Diseases, Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0161-7814","authenticated-orcid":false,"given":"Alexandria P.","family":"Eiken","sequence":"additional","affiliation":[{"name":"Eppley Institute for Research in Cancer and Allied Diseases, Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sydney A.","family":"Skupa","sequence":"additional","affiliation":[{"name":"Eppley Institute for Research in Cancer and Allied Diseases, Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1987-4472","authenticated-orcid":false,"given":"Dalia Y.","family":"Moore","sequence":"additional","affiliation":[{"name":"Eppley Institute for Research in Cancer and Allied Diseases, Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lelisse T.","family":"Umeta","sequence":"additional","affiliation":[{"name":"Eppley Institute for Research in Cancer and Allied Diseases, Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lynette M.","family":"Smith","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, College of Public Health, University of Nebraska Medical Center, Omaha, NE 68198, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elizabeth R.","family":"Lyden","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, College of Public Health, University of Nebraska Medical Center, Omaha, NE 68198, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christopher R.","family":"D\u2019Angelo","sequence":"additional","affiliation":[{"name":"Division of Hematology and Oncology, Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Avyakta","family":"Kallam","sequence":"additional","affiliation":[{"name":"Division of Hematology and Oncology, Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1015-7434","authenticated-orcid":false,"given":"Julie M.","family":"Vose","sequence":"additional","affiliation":[{"name":"Division of Hematology and Oncology, Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tatiana G.","family":"Kutateladze","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO 80045, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1083-8283","authenticated-orcid":false,"given":"Dalia","family":"El-Gamal","sequence":"additional","affiliation":[{"name":"Eppley Institute for Research in Cancer and Allied Diseases, Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,6,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"16096","DOI":"10.1038\/nrdp.2016.96","article-title":"Chronic lymphocytic leukaemia","volume":"3","author":"Kipps","year":"2017","journal-title":"Nat. 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