Akt, a serine‐threonine protein kinase, is regulated by class‐I PI3K signaling. Akt regulates a wide variety of cell processes including cell proliferation, survival, and angiogenesis through serine/threonine phosphorylation of downstream targets including mTOR and glycogen‐synthase‐kinase‐3‐beta (GSK3β). Targeting cancer‐specific overexpression of Akt protein could be an efficient way to control cancer‐cell proliferation. However, the ATP‐competitive inhibitors are challenged by the highly conserved ATP binding site, and by competition with high cellular concentrations of ATP. We previously developed an allosteric inhibitor, 2‐arylidene‐4, 7‐dimethyl indan‐1‐one (FXY‐1) that showed promising activity against several lung cancer models. In this work, we designed a congeneric series of molecules based on FXY‐1 and optimized lead based on computational, in vitro assays. Computational screening followed by enzyme‐inhibition and cell‐proliferation assays identified a derivative (FCX‐146) as a new lead molecule with threefold greater potency than the parent compound. FCX‐146 increased apoptosis in HL‐60 cells, mediated in part through decreased expression of antiapoptotic Bcl‐2 protein and increased levels of Bax‐2 and Caspase‐3. Molecular‐dynamic simulations showed stable binding of FCX‐146 to an allosteric (i.e., noncatalytic) pocket in Akt. Together, we propose FCX‐146 as a potent second‐generation arylidene indanone compound that binds to the allosteric pocket of Akt and potently inhibits its activation.

中文翻译：

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FCX-146，一种有效的癌细胞Akt激酶变构抑制剂：第二代芳基茚满酮骨架的前导优化

Akt是一种丝氨酸-苏氨酸蛋白激酶，受I类PI3K信号传导调控。Akt通过下游靶标（包括mTOR和糖原合酶激酶3-β（GSK3β））的丝氨酸/苏氨酸磷酸化来调节多种细胞过程，包括细胞增殖，存活和血管生成。针对癌症特异性的Akt蛋白过度表达可能是控制癌细胞增殖的有效方法。但是，ATP竞争性抑制剂受到高度保守的ATP结合位点以及与高细胞浓度ATP竞争的挑战。我们以前开发了一种变构抑制剂2-亚芳基-4、7-二甲基茚满1-1（FXY-1），它对多种肺癌模型均显示出令人鼓舞的活性。在这项工作中，体外测定。通过计算机筛选，然后进行酶抑制和细胞增殖测定，鉴定出一种衍生物（FCX-146）作为一种新的先导分子，其效力比母体化合物高三倍。FCX-146增加了HL-60细胞的凋亡，部分是通过降低抗凋亡Bcl-2蛋白的表达以及增加Bax-2和Caspase-3的水平来介导的。分子动力学模拟表明，FCX-146与Akt的变构（即非催化）口袋稳定结合。我们共同提出FCX-146作为有效的第二代亚芳基茚满酮化合物，该化合物与Akt的变构口袋结合并有效抑制其活化。