{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T10:16:51Z","timestamp":1778581011791,"version":"3.51.4"},"reference-count":54,"publisher":"Public Library of Science (PLoS)","issue":"3","license":[{"start":{"date-parts":[[2023,3,8]],"date-time":"2023-03-08T00:00:00Z","timestamp":1678233600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100017468","name":"Aptose Biosciences","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100017468","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Luxeptinib (LUX) is a novel oral kinase inhibitor that inhibits FLT3 and also interferes with signaling from the BCR and cell surface TLRs, as well as activation of the NLRP3 inflammasome. Ongoing clinical trials are testing its activity in patients with lymphoma and AML. This study sought to refine understanding of how LUX modulates the earliest steps downstream of the BCR following its activation by anti-IgM in lymphoma cells in comparison to ibrutinib (IB). LUX decreased anti-IgM-induced phosphorylation of BTK at Y551 and Y223 but its ability to reduce phosphorylation of kinases further upstream suggests that BTK is not the primary target. LUX was more effective than IB at reducing both steady state and anti-IgM-induced phosphorylation of LYN and SYK. LUX decreased phosphorylation of SYK (Y525\/Y526) and BLNK (Y96) which are necessary regulators of BTK activation. Further upstream, LUX blunted the anti-IgM-induced phosphorylation of LYN (Y397) whose activation is required for phosphorylation of SYK and BLNK. These results indicate that LUX is targeting autophosphorylation of LYN or a step further upstream of LYN in the cascade of signal generated by BCR and that it does so more effectively than IB. The fact that LUX has activity at or upstream of LYN is important because LYN is an essential signaling intermediate in multiple cellular signaling processes that regulate growth, differentiation, apoptosis, immunoregulation, migration and EMT in normal and cancer cells.<\/jats:p>","DOI":"10.1371\/journal.pone.0277003","type":"journal-article","created":{"date-parts":[[2023,3,8]],"date-time":"2023-03-08T18:35:48Z","timestamp":1678300548000},"page":"e0277003","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":6,"title":["Luxeptinib interferes with LYN-mediated activation of SYK and modulates BCR signaling in lymphoma"],"prefix":"10.1371","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2977-7636","authenticated-orcid":true,"given":"Himangshu","family":"Sonowal","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"William G.","family":"Rice","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0877-8226","authenticated-orcid":true,"given":"Stephen B.","family":"Howell","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2023,3,8]]},"reference":[{"key":"pone.0277003.ref001","doi-asserted-by":"crossref","first-page":"429","DOI":"10.12688\/f1000research.13567.1","article-title":"Role of B-cell receptors for B-cell development and antigen-induced differentiation","volume":"7","author":"JC Yam-Puc","year":"2018","journal-title":"F1000Research"},{"issue":"1","key":"pone.0277003.ref002","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1186\/s12943-018-0779-z","article-title":"Role of Bruton\u2019s tyrosine kinase in B cells and malignancies","volume":"17","author":"S Pal Singh","year":"2018","journal-title":"Molecular Cancer"},{"issue":"3","key":"pone.0277003.ref003","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1038\/nrc.2017.121","article-title":"Targeting B cell receptor signalling in cancer: preclinical and clinical advances","volume":"18","author":"JA Burger","year":"2018","journal-title":"Nature reviews Cancer"},{"key":"pone.0277003.ref004","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1038\/ni893","article-title":"Essential role of Src-family protein tyrosine kinases in NF-kappaB activation during B cell development","volume":"4","author":"K Saijo","year":"2003","journal-title":"Nature immunology"},{"issue":"1","key":"pone.0277003.ref005","first-page":"9","article-title":"Lyn tyrosine kinase: accentuating the positive and the negative","volume":"22","author":"Y Xu","year":"2005","journal-title":"Immunity"},{"issue":"2","key":"pone.0277003.ref006","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1083\/jcb.200802007","article-title":"Membrane heterogeneities in the formation of B cell receptor-Lyn kinase microclusters and the immune synapse","volume":"182","author":"HW Sohn","year":"2008","journal-title":"The Journal of cell biology"},{"issue":"5","key":"pone.0277003.ref007","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1016\/S1074-7613(00)80568-3","article-title":"CD19 as a membrane-anchored adaptor protein of B lymphocytes: costimulation of lipid and protein kinases by recruitment of Vav","volume":"8","author":"LM O\u2019Rourke","year":"1998","journal-title":"Immunity"},{"issue":"19","key":"pone.0277003.ref008","doi-asserted-by":"crossref","first-page":"16201","DOI":"10.1074\/jbc.M100873200","article-title":"Interaction between the Btk PH domain and phosphatidylinositol-3,4,5-trisphosphate directly regulates Btk","volume":"276","author":"K Saito","year":"2001","journal-title":"The Journal of biological chemistry"},{"issue":"1","key":"pone.0277003.ref009","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1016\/S1074-7613(00)80591-9","article-title":"BLNK: a central linker protein in B cell activation","volume":"9","author":"C Fu","year":"1998","journal-title":"Immunity"},{"issue":"5","key":"pone.0277003.ref010","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1038\/nri801","article-title":"Regulation of B-cell signal transduction by adaptor proteins","volume":"2","author":"T. Kurosaki","year":"2002","journal-title":"Nature Reviews Immunology"},{"issue":"5","key":"pone.0277003.ref011","doi-asserted-by":"crossref","first-page":"2582","DOI":"10.1073\/pnas.051626198","article-title":"BLNK mediates Syk-dependent Btk activation","volume":"98","author":"Y Baba","year":"2001","journal-title":"Proceedings of the National Academy of Sciences of the United States of America"},{"issue":"25","key":"pone.0277003.ref012","doi-asserted-by":"crossref","first-page":"15595","DOI":"10.1074\/jbc.272.25.15595","article-title":"Transphosphorylation of Bruton\u2019s tyrosine kinase on tyrosine 551 is critical for B cell antigen receptor function","volume":"272","author":"T Kurosaki","year":"1997","journal-title":"The Journal of biological chemistry"},{"issue":"3","key":"pone.0277003.ref013","doi-asserted-by":"crossref","DOI":"10.1101\/cshperspect.a002352","article-title":"Src-family and Syk kinases in activating and inhibitory pathways in innate immune cells: signaling cross talk","volume":"3","author":"CA Lowell","year":"2011","journal-title":"Cold Spring Harbor perspectives in biology"},{"issue":"3","key":"pone.0277003.ref014","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1111\/ejh.12427","article-title":"B-cell receptor signalling and its crosstalk with other pathways in normal and malignant cells","volume":"94","author":"V Seda","year":"2015","journal-title":"European journal of haematology"},{"issue":"6","key":"pone.0277003.ref015","doi-asserted-by":"crossref","first-page":"957","DOI":"10.2217\/fon.14.51","article-title":"Ibrutinib: a first in class covalent inhibitor of Bruton\u2019s tyrosine kinase","volume":"10","author":"MS Davids","year":"2014","journal-title":"Future oncology (London, England)"},{"key":"pone.0277003.ref016","doi-asserted-by":"crossref","first-page":"737943","DOI":"10.3389\/fonc.2021.737943","article-title":"Clinical Trials of the BTK Inhibitors Ibrutinib and Acalabrutinib in Human Diseases Beyond B Cell Malignancies","volume":"11","author":"S Zhu","year":"2021","journal-title":"Frontiers in oncology"},{"issue":"7","key":"pone.0277003.ref017","doi-asserted-by":"crossref","first-page":"1454","DOI":"10.4049\/jimmunol.2001130","article-title":"Preclinical Efficacy and Anti-Inflammatory Mechanisms of Action of the Bruton Tyrosine Kinase Inhibitor Rilzabrutinib for Immune-Mediated Disease","volume":"206","author":"CL Langrish","year":"2021","journal-title":"Journal of immunology (Baltimore, Md: 1950)"},{"issue":"7","key":"pone.0277003.ref018","doi-asserted-by":"crossref","first-page":"581","DOI":"10.4049\/immunohorizons.2100063","article-title":"Preclinical Mechanisms of Topical PRN473, a Bruton Tyrosine Kinase Inhibitor, in Immune-Mediated Skin Disease Models","volume":"5","author":"Y Xing","year":"2021","journal-title":"ImmunoHorizons"},{"issue":"10","key":"pone.0277003.ref019","doi-asserted-by":"crossref","first-page":"2888","DOI":"10.4049\/jimmunol.1800583","article-title":"Efficacy and Pharmacodynamic Modeling of the BTK Inhibitor Evobrutinib in Autoimmune Disease Models","volume":"202","author":"P Haselmayer","year":"2019","journal-title":"Journal of immunology (Baltimore, Md: 1950)"},{"key":"pone.0277003.ref020","doi-asserted-by":"crossref","first-page":"1454","DOI":"10.3389\/fimmu.2017.01454","article-title":"Bruton\u2019s Tyrosine Kinase: An Emerging Key Player in Innate Immunity","volume":"8","author":"ANR Weber","year":"2017","journal-title":"Frontiers in immunology"},{"key":"pone.0277003.ref021","doi-asserted-by":"crossref","first-page":"668131","DOI":"10.3389\/fcell.2021.668131","article-title":"Targeting Bruton\u2019s Tyrosine Kinase in Inflammatory and Autoimmune Pathologies","volume":"9","author":"SFH Neys","year":"2021","journal-title":"Frontiers in cell and developmental biology"},{"issue":"2","key":"pone.0277003.ref022","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1016\/j.pharmthera.2013.02.001","article-title":"Targeting the SYK-BTK axis for the treatment of immunological and hematological disorders: recent progress and therapeutic perspectives","volume":"138","author":"SL Tan","year":"2013","journal-title":"Pharmacology & therapeutics"},{"key":"pone.0277003.ref023","doi-asserted-by":"crossref","first-page":"114232","DOI":"10.1016\/j.ejmech.2022.114232","article-title":"Recent development of BTK-based dual inhibitors in the treatment of cancers","volume":"233","author":"F Ran","year":"2022","journal-title":"European journal of medicinal chemistry"},{"issue":"15","key":"pone.0277003.ref024","doi-asserted-by":"crossref","first-page":"1421","DOI":"10.1056\/NEJMoa2110297","article-title":"Rilzabrutinib, an Oral BTK Inhibitor, in Immune Thrombocytopenia","volume":"386","author":"DJ Kuter","year":"2022","journal-title":"The New England journal of medicine"},{"issue":"7","key":"pone.0277003.ref025","doi-asserted-by":"crossref","first-page":"1125","DOI":"10.1158\/1535-7163.MCT-21-0832","article-title":"Luxeptinib (CG-806) Targets FLT3 and Clusters of Kinases Operative in Acute Myeloid Leukemia","volume":"21","author":"WG Rice","year":"2022","journal-title":"Molecular cancer therapeutics"},{"issue":"3","key":"pone.0277003.ref026","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1038\/s41419-022-04684-1","article-title":"Dual BTK\/SYK inhibition with CG-806 (luxeptinib) disrupts B-cell receptor and Bcl-2 signaling networks in mantle cell lymphoma","volume":"13","author":"E Thieme","year":"2022","journal-title":"Cell death & disease"},{"issue":"4","key":"pone.0277003.ref027","doi-asserted-by":"crossref","first-page":"791","DOI":"10.1084\/jem.188.4.791","article-title":"SLP-65: a new signaling component in B lymphocytes which requires expression of the antigen receptor for phosphorylation","volume":"188","author":"J Wienands","year":"1998","journal-title":"The Journal of experimental medicine"},{"issue":"23","key":"pone.0277003.ref028","doi-asserted-by":"crossref","first-page":"6461","DOI":"10.1093\/emboj\/cdf658","article-title":"BLNK: molecular scaffolding through \u2019cis\u2019-mediated organization of signaling proteins","volume":"21","author":"CW Chiu","year":"2002","journal-title":"The EMBO journal"},{"issue":"10","key":"pone.0277003.ref029","doi-asserted-by":"crossref","first-page":"825","DOI":"10.1046\/j.1365-2443.2003.00679.x","article-title":"Negative regulation of Lyn protein-tyrosine kinase by c-Cbl ubiquitin-protein ligase in Fc epsilon RI-mediated mast cell activation","volume":"8","author":"S Kyo","year":"2003","journal-title":"Genes to cells: devoted to molecular & cellular mechanisms"},{"key":"pone.0277003.ref030","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1146\/annurev.cellbio.13.1.513","article-title":"Cellular functions regulated by Src family kinases","volume":"13","author":"SM Thomas","year":"1997","journal-title":"Annual review of cell and developmental biology"},{"issue":"2\u20133","key":"pone.0277003.ref031","first-page":"121","article-title":"Regulation, substrates and functions of src","volume":"1287","author":"MT Brown","year":"1996","journal-title":"Biochimica et biophysica acta"},{"key":"pone.0277003.ref032","doi-asserted-by":"crossref","first-page":"114861","DOI":"10.1016\/j.bcp.2021.114861","article-title":"Luxeptinib disables NLRP3 inflammasome-mediated IL-1\u03b2 release and pathways required for secretion of inflammatory cytokines IL-6 and TNF\u03b1","volume":"195","author":"H Sonowal","year":"2022","journal-title":"Biochemical pharmacology"},{"issue":"Supplement 1","key":"pone.0277003.ref033","doi-asserted-by":"crossref","first-page":"1355","DOI":"10.1182\/blood-2021-148827","article-title":"A Phase 1a\/b Dose Escalation Study of the Mutation Agnostic BTK\/FLT3 Inhibitor Luxeptinib (CG-806) in Patients with Relapsed or Refractory B-Cell Malignancies","volume":"138","author":"F Samaniego","year":"2021","journal-title":"Blood"},{"key":"pone.0277003.ref034","doi-asserted-by":"crossref","first-page":"1272","DOI":"10.1182\/blood-2021-149333","article-title":"A Phase 1a\/b Dose Escalation Study of the Mutation Agnostic FLT3\/BTK Inhibitor Luxeptinib (CG-806) in Patients with Relapsed or Refractory Acute Myeloid Leukemia","volume":"138","author":"AD Goldberg","year":"2021","journal-title":"Blood"},{"issue":"13_Supplement","key":"pone.0277003.ref035","doi-asserted-by":"crossref","first-page":"794","DOI":"10.1158\/1538-7445.AM2018-794","article-title":"Abstract 794: CG\u2019806, a first-in-class pan-FLT3\/pan-BTK inhibitor, targets multiple pathways to kill diverse subtypes of acute myeloid leukemia and B-cell malignancy in vitro","volume":"78","author":"H Zhang","year":"2018","journal-title":"Cancer Research"},{"issue":"5","key":"pone.0277003.ref036","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1016\/S1074-7613(00)80417-3","article-title":"Regulation of Btk function by a major autophosphorylation site within the SH3 domain","volume":"4","author":"H Park","year":"1996","journal-title":"Immunity"},{"issue":"5250","key":"pone.0277003.ref037","doi-asserted-by":"crossref","first-page":"822","DOI":"10.1126\/science.271.5250.822","article-title":"Activation of BTK by a phosphorylation mechanism initiated by SRC family kinases","volume":"271","author":"DJ Rawlings","year":"1996","journal-title":"Science (New York, NY)"},{"issue":"5","key":"pone.0277003.ref038","doi-asserted-by":"crossref","first-page":"1725","DOI":"10.1084\/jem.179.5.1725","article-title":"Syk activation by the Src-family tyrosine kinase in the B cell receptor signaling","volume":"179","author":"T Kurosaki","year":"1994","journal-title":"The Journal of experimental medicine"},{"issue":"45","key":"pone.0277003.ref039","doi-asserted-by":"crossref","first-page":"35442","DOI":"10.1074\/jbc.M004549200","article-title":"Phosphorylation of Syk activation loop tyrosines is essential for Syk function. An in vivo study using a specific anti-Syk activation loop phosphotyrosine antibody","volume":"275","author":"J Zhang","year":"2000","journal-title":"The Journal of biological chemistry"},{"issue":"46","key":"pone.0277003.ref040","doi-asserted-by":"crossref","first-page":"32662","DOI":"10.1074\/jbc.274.46.32662","article-title":"SYK is upstream of phosphoinositide 3-kinase in B cell receptor signaling","volume":"274","author":"LO Beitz","year":"1999","journal-title":"The Journal of biological chemistry"},{"issue":"5","key":"pone.0277003.ref041","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1517\/13543784.2011.570329","article-title":"The Syk kinase as a therapeutic target in leukemia and lymphoma","volume":"20","author":"DG Efremov","year":"2011","journal-title":"Expert opinion on investigational drugs"},{"issue":"1","key":"pone.0277003.ref042","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1016\/S1074-7613(00)80012-6","article-title":"BLNK required for coupling Syk to PLC gamma 2 and Rac1-JNK in B cells","volume":"10","author":"M Ishiai","year":"1999","journal-title":"Immunity"},{"issue":"8","key":"pone.0277003.ref043","doi-asserted-by":"crossref","first-page":"578","DOI":"10.1038\/nri3487","article-title":"New insights into pre-BCR and BCR signalling with relevance to B cell malignancies","volume":"13","author":"RC Rickert","year":"2013","journal-title":"Nature Reviews Immunology"},{"key":"pone.0277003.ref044","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1146\/annurev.iy.12.040194.002325","article-title":"Signal transduction by the B cell antigen receptor and its coreceptors","volume":"12","author":"JC Cambier","year":"1994","journal-title":"Annual review of immunology"},{"key":"pone.0277003.ref045","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1146\/annurev.immunol.15.1.453","article-title":"Initiation and processing of signals from the B cell antigen receptor","volume":"15","author":"M Reth","year":"1997","journal-title":"Annual review of immunology"},{"issue":"4990","key":"pone.0277003.ref046","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1126\/science.1702903","article-title":"Association of B cell antigen receptor with protein tyrosine kinase Lyn","volume":"251","author":"Y Yamanashi","year":"1991","journal-title":"Science (New York, NY)"},{"issue":"4","key":"pone.0277003.ref047","doi-asserted-by":"crossref","first-page":"1402","DOI":"10.1073\/pnas.90.4.1402","article-title":"Correlation between Src family member regulation by the protein-tyrosine-phosphatase CD45 and transmembrane signaling through the T-cell receptor","volume":"90","author":"ED Cahir McFarland","year":"1993","journal-title":"Proceedings of the National Academy of Sciences of the United States of America"},{"issue":"11","key":"pone.0277003.ref048","first-page":"7306","article-title":"Functional analysis of Csk in signal transduction through the B-cell antigen receptor","volume":"14","author":"A Hata","year":"1994","journal-title":"Molecular and cellular biology"},{"issue":"5","key":"pone.0277003.ref049","doi-asserted-by":"crossref","first-page":"1438","DOI":"10.1021\/bi971332s","article-title":"Spontaneous autophosphorylation of Lyn tyrosine kinase at both its activation segment and C-terminal tail confers altered substrate specificity","volume":"37","author":"A Donella-Deana","year":"1998","journal-title":"Biochemistry"},{"issue":"50","key":"pone.0277003.ref050","doi-asserted-by":"crossref","first-page":"29773","DOI":"10.1074\/jbc.270.50.29773","article-title":"Autophosphorylation induces autoactivation and a decrease in the Src homology 2 domain accessibility of the Lyn protein kinase","volume":"270","author":"N Sotirellis","year":"1995","journal-title":"The Journal of biological chemistry"},{"issue":"49","key":"pone.0277003.ref051","doi-asserted-by":"crossref","first-page":"5620","DOI":"10.1038\/sj.onc.1203923","article-title":"Selected glimpses into the activation and function of Src kinase","volume":"19","author":"JD Bjorge","year":"2000","journal-title":"Oncogene"},{"issue":"5","key":"pone.0277003.ref052","first-page":"365","article-title":"SH3-dependent stimulation of Src-family kinase autophosphorylation without tail release from the SH2 domain in vivo","volume":"9","author":"EC Lerner","year":"2002","journal-title":"Nature structural biology"},{"issue":"10","key":"pone.0277003.ref053","doi-asserted-by":"crossref","DOI":"10.1210\/endocr\/bqab152","article-title":"The Src-family Kinase Lyn in Immunoreceptor Signaling","volume":"162","author":"BF Brian","year":"2021","journal-title":"Endocrinology"},{"key":"pone.0277003.ref054","doi-asserted-by":"crossref","first-page":"1862","DOI":"10.3389\/fimmu.2019.01862","article-title":"Tyrosine Kinases in Autoimmune and Inflammatory Skin Diseases","volume":"10","author":"KP Szilveszter","year":"2019","journal-title":"Frontiers in immunology"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0277003","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,3,8]],"date-time":"2023-03-08T18:36:26Z","timestamp":1678300586000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0277003"}},"subtitle":[],"editor":[{"given":"Laszlo","family":"Buday","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2023,3,8]]},"references-count":54,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2023,3,8]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0277003","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,3,8]]}}}