Defects in the phosphoinositide 3-kinase (PI3K) pathway are shared characteristics in several brain disorders, including the inherited intellectual disability and autism spectrum disorder, fragile X syndrome (FXS). PI3K signaling therefore could serve as a therapeutic target for FXS and other brain disorders. However, broad inhibition of such a central signal transduction pathway involved in essential cellular functions may produce deleterious side effects. Pharmacological strategies that selectively correct the overactive components of the PI3K pathway while leaving other parts of the pathway intact may overcome these challenges. Here, we provide the first evidence that disease mechanism-based PI3K isoform-specific inhibition may be a viable treatment option for FXS. FXS is caused by loss of the fragile X mental retardation protein (FMRP), which translationally represses specific messenger RNAs, including the PI3K catalytic isoform p110β. FMRP deficiency increases p110β protein levels and activity in FXS mouse models and in cells from subjects with FXS. Here, we show that a novel, brain-permeable p110β-specific inhibitor, GSK2702926A, ameliorates FXS-associated phenotypes on molecular, cellular, behavioral, and cognitive levels in two different FMRP-deficient mouse models. Rescued phenotypes included increased PI3K downstream signaling, protein synthesis rates, and dendritic spine density, as well as impaired social interaction and higher-order cognition. Several p110β-selective inhibitors, for example, a molecule from the same chemotype as GSK2702926A, are currently being evaluated in clinical trials to treat cancer. Our results suggest that repurposing p110β inhibitors to treat cognitive and behavioral defects may be a promising disease-modifying strategy for FXS and other brain disorders.

中文翻译：

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异构体选择性磷酸肌醇 3-激酶抑制可改善小鼠模型中广泛的脆性 X 综合征相关缺陷。

磷酸肌醇 3-激酶 (PI3K) 通路的缺陷是几种脑部疾病的共同特征，包括遗传性智力障碍和自闭症谱系障碍、脆性 X 综合征 (FXS)。因此，PI3K 信号可以作为 FXS 和其他脑部疾病的治疗靶点。然而，广泛抑制这种涉及基本细胞功能的中央信号转导途径可能会产生有害的副作用。选择性地纠正 PI3K 通路的过度活跃成分，同时保持通路的其他部分完好无损的药理学策略可能会克服这些挑战。在这里，我们提供了第一个证据，表明基于疾病机制的 PI3K 亚型特异性抑制可能是 FXS 的可行治疗选择。FXS 是由脆性 X 智力迟钝蛋白 (FMRP) 的丢失引起的，它在翻译上抑制特定的信使 RNA，包括 PI3K 催化异构体 p110β。FMRP 缺乏会增加 FXS 小鼠模型和 FXS 受试者细胞中的 p110β 蛋白水平和活性。在这里，我们展示了一种新型的脑渗透性 p110β 特异性抑制剂 GSK2702926A 在两种不同的 FMRP 缺陷小鼠模型中改善了分子、细胞、行为和认知水平上的 FXS 相关表型。获救的表型包括 PI3K 下游信号传导、蛋白质合成率和树突棘密度增加，以及社交互动和高级认知受损。几种 p110β 选择性抑制剂，例如与 GSK2702926A 具有相同化学型的分子，目前正在临床试验中进行评估以治疗癌症。