靶向抑制bromodomain和extraterminal（BET）-bromodomain以及磷酸肌醇-3-激酶（PI3K）信号传导，作为单独药物在细胞髓细胞瘤（cMYC）癌基因失常环境中表现出的有效但自限抗淋巴瘤活性。然而，PI3K和BET的联合抑制具有协同的抗癌活性，在补偿性表观遗传和信号网络相互对抗的背景下有潜力产生更持久的疾病反应。在这里，我们描述了理性设计的双重PI3K/BET bromodomain抑制剂的机械和治疗的验证，通过链接已建立的PI3K和BET抑制剂药效团。领先的候选药物表现出高选择性，纳摩尔级细胞效力和令人信服的体内功效，包括在侵略性Eµ-Myc淋巴瘤模型中的治愈反应。这些研究进一步支持联合PI3K和BET抑制的治疗策略，并提供使用优化的嵌合小分子技术进行正交MYC拮抗的潜在步变方法。

Targeted inhibitors of bromodomain and extraterminal (BET)-bromodomains and phosphatidylinositol-3-kinase (PI3K) signaling demonstrate potent but self-limited antilymphoma activity as single agents in the context of cellular Myelocytomatosis (cMYC) oncogene-dysregulation. However, combined PI3K and BET inhibition imparts synergistic anticancer activity with the potential for more sustained disease responses due to the mutual antagonism of compensatory epigenetic and signaling networks. Here, we describe the mechanistic and therapeutic validation of rationally designed dual PI3K/BET bromodomain inhibitors, built by linkage of established PI3K and BET inhibitor pharmacophores. The lead candidate demonstrates high selectivity, nanomolar range cellular potency, and compelling in vivo efficacy, including curative responses in the aggressive Eµ-Myc lymphoma model. These studies further support the therapeutic strategy of combined PI3K and BET inhibition and provide a potential step-change in approach to orthogonal MYC antagonism using optimized chimeric small-molecule technology.