Mantle 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 potent in vitro and in vivo activity 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 in in vivo xenograft 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.

套细胞淋巴瘤 (MCL) 是非霍奇金淋巴瘤的一种侵袭性亚型，由于治疗后频繁复发，因此是最具挑战性的血癌之一。在这里，我们开发了一流的 BTK/PI3K/BRD4 轴抑制剂 SRX3262，它同时阻断了三个相互关联的 MCL 驱动途径——BTK、PI3K-AKT-mTOR 和 MYC。SRX3262 同时与 BTK、PI3K 和 BRD4 结合，表现出对 MCL 的有效体外和体内活性，并克服了由 BTK-C481S 突变引起的依鲁替尼耐药性。我们的结果表明，SRX3262 抑制 IgM 诱导的 BTK 和 AKT 磷酸化并消除 BRD4 与 MYC 基因座的结合。SRX3262 促进 c-MYC 去稳定化，诱导细胞周期停滞和凋亡，并在体内显示出抗肿瘤活性异种移植模型。总之，我们的研究为使用三重 BTK/PI3K/BRD4 活性抑制剂作为治疗 MCL 的新方法提供了机理见解和基本原理。