摘要：SummaryMantle cell lymphoma (MCL) is an aggressive subtype of non-Hodgkin's lymphoma and one of the most challenging blood cancers to combat due to frequent relapse after treatment. Here, we developed the first-in-class BTK/PI3K/BRD4 axis inhibitor SRX3262, which simultaneously blocks three interrelated MCL driver pathways – BTK, PI3K-AKT-mTOR and MYC. SRX3262 concomitantly binds to BTK, PI3K, and BRD4, exhibits potentin vitroandin vivoactivity against MCL, and overcomes the Ibrutinib resistance resulting from the BTK-C481S mutation. Our results reveal that SRX3262 inhibits IgM-induced BTK and AKT phosphorylation and abrogates binding of BRD4 to MYC loci. SRX3262 promotes c-MYC destabilization, induces cell cycle arrest and apoptosis, and shows antitumor activity inin vivoxenograft models. Together, our study provides mechanistic insights and rationale for the use of the triple BTK/PI3K/BRD4 activity inhibitors as a new approach to treat MCL.Graphical abstractDisplay OmittedHighlights•BTK/PI3K/BRD4 axis inhibitor SRX3262 simultaneously blocks three MCL driver pathways•SRX3262 binds to BTK, PI3K, and BRD4 and exhibits potent anti-MCL activityin vivo•SRX3262 inhibits BTK and AKT phosphorylation and abrogates binding of BRD4 to MYC•SRX3262 promotes c-MYC destabilization and induces cell cycle arrest and apoptosisMedical biochemistry; Molecular physiology; Cancer;
