Functional characterization of an isoform-selective inhibitor of PI3K-p110β as a potential anticancer agent.
Functional characterization of an isoform-selective inhibitor of PI3K-p110β as a potential anticancer agent.
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DOI：
10.1158/2159-8290.cd-12-0003
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发表时间：
2012-05
期刊：
影响因子：
28.2
通讯作者：
Zhao J
中科院分区：
文献类型：
--
作者：
Ni J;Liu Q;Xie S;Carlson C;Von T;Vogel K;Riddle S;Benes C;Eck M;Roberts T;Gray N;Zhao J
遗传学方法已经证明PI 3 K的p110β亚型对于PTEN缺失肿瘤的生长至关重要。因此，需要开发用于癌症治疗的p110β特异性抑制剂。使用一组PI 3 K亚型特异性细胞测定，我们筛选了一系列具有PI 3 K超家族激酶活性的化合物，并鉴定了一种有效的选择性p110β抑制剂：KIN-193。我们发现KIN-193在阻断依赖于p110β激活或PTEN丢失的AKT信号传导和肿瘤生长方面是有效的。一组422种人类肿瘤细胞系的广泛分析表明，癌细胞的PTEN突变状态与其对KIN-193的反应密切相关。总之，我们的数据提供了第一个药理学证据，证明PTEN缺陷型肿瘤在动物中依赖于p110β，并表明KIN-193可以作为一种药物来治疗依赖于p110β的肿瘤，同时保留其他PI 3 K亚型。
Genetic approaches have demonstrated that the p110β isoform of PI3K is essential for the growth of PTEN-null tumors. Thus, it is desirable to develop p110β-specific inhibitors for cancer therapy. Using a panel of PI3K isoform-specific cellular assays, we screened a collection of compounds possessing activities against kinases in the PI3K superfamily and identified a potent and selective p110β inhibitor: KIN-193. We show that KIN-193 is efficacious specifically in blocking AKT signaling and tumor growth that are dependent on p110β activation or PTEN-loss. Broad profiling across a panel of 422 human tumor cell lines demonstrates that the PTEN mutation status of cancer cells strongly correlates with their response to KIN-193. Together, our data provide the first pharmacological evidence that PTEN-deficient tumors are dependent on p110β in animals, and suggest that KIN-193 can be pursued as a drug to treat tumors that are dependent on p110β, while sparing other PI3K isoforms.