Identification of 4-phenylquinolin-2(1H)-one as a specific allosteric inhibitor of Akt.
Identification of 4-phenylquinolin-2(1H)-one as a specific allosteric inhibitor of Akt.
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DOI：
10.1038/s41598-017-11870-1
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发表时间：
2017-09-15
影响因子：
4.6
通讯作者：
Kim HY
中科院分区：
文献类型：
--
作者：
Huang BX;Newcomer K;Kevala K;Barnaeva E;Zheng W;Hu X;Patnaik S;Southall N;Marugan J;Ferrer M;Kim HY
AKT在肿瘤的发生中起着重要的作用，而开发特异性的Akt抑制剂作为有效的癌症治疗药物一直是具有挑战性的。在这里，我们报道了通过基于FRET的高通量筛选鉴定出一种高度特异的Akt变构抑制剂，并对其抑制机制进行了表征。在筛选的373,868个化合物中，4-苯基喹啉-2(1H)-酮特异性地降低了T308和S473处的Akt磷酸化，并抑制了Akt激酶活性(IC50 = 6 µM)和下游信号转导。4-苯基喹啉-2(1H)-酮不改变上游的PI3K、PDK1和mTORC2以及影响细胞增殖和存活的密切相关的激酶如SGK1、PKA、PKC或ERK1/2的活性。该化合物抑制癌细胞的增殖，但与PI3K或mTOR的抑制剂相比毒性较小。激酶图谱分析表明，4-苯基喹啉-2(1H)-酮不与包括Akt在内的380多个人类激酶的活性部位结合。然而，4-苯基喹啉-2(1H)-酮与Akt的PH结构域相互作用，明显地诱导了一种构象，阻碍了mTORC2和PDK1对S473和T308的磷酸化。综上所述，我们证明了4-苯基喹啉-2(1H)-酮是一种选择性很好的Akt抑制剂，具有独特的分子机制，是一种有前途的先导化合物，可用于进一步优化开发新的癌症治疗药物。
Akt plays a major role in tumorigenesis and the development of specific Akt inhibitors as effective cancer therapeutics has been challenging. Here, we report the identification of a highly specific allosteric inhibitor of Akt through a FRET-based high-throughput screening, and characterization of its inhibitory mechanism. Out of 373,868 compounds screened, 4-phenylquinolin-2(1H)-one specifically decreased Akt phosphorylation at both T308 and S473, and inhibited Akt kinase activity (IC50 = 6 µM) and downstream signaling. 4-Phenylquinolin-2(1H)-one did not alter the activity of upstream kinases including PI3K, PDK1, and mTORC2 as well as closely related kinases that affect cell proliferation and survival such as SGK1, PKA, PKC, or ERK1/2. This compound inhibited the proliferation of cancer cells but displayed less toxicity compared to inhibitors of PI3K or mTOR. Kinase profiling efforts revealed that 4-phenylquinolin-2(1H)-one does not bind to the kinase active site of over 380 human kinases including Akt. However, 4-phenylquinolin-2(1H)-one interacted with the PH domain of Akt, apparently inducing a conformation that hinders S473 and T308 phosphorylation by mTORC2 and PDK1. In conclusion, we demonstrate that 4-phenylquinolin-2(1H)-one is an exquisitely selective Akt inhibitor with a distinctive molecular mechanism, and a promising lead compound for further optimization toward the development of novel cancer therapeutics.
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影响因子：
4.6
作者：
Lindhurst MJ;Yourick MR;Yu Y;Savage RE;Ferrari D;Biesecker LG
通讯作者：
Biesecker LG
影响因子：
64.5
作者：
Brunet, A;Bonni, A;Greenberg, ME
通讯作者：
Greenberg, ME
影响因子：
7
作者：
Huang, Bill X.;Kim, Hee-Yong
通讯作者：
Kim, Hee-Yong
影响因子：
4.8
作者：
Hiromura, M;Okada, F;Noguchi, M
通讯作者：
Noguchi, M
DOI：
10.1016/j.jasms.2009.04.004
发表时间：
2009-08-01
影响因子：
3.2
作者：
Huang, Bill X.;Kim, Hee-Yong
通讯作者：
Kim, Hee-Yong