Cancer Network Disruption by a Single Molecule Inhibitor Targeting Both Histone Deacetylase Activity and Phosphatidylinositol 3-Kinase Signaling
Cancer Network Disruption by a Single Molecule Inhibitor Targeting Both Histone Deacetylase Activity and Phosphatidylinositol 3-Kinase Signaling
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DOI：
10.1158/1078-0432.ccr-12-0055
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发表时间：
2012-08-01
影响因子：
11.5
通讯作者：
Voi, Maurizio
中科院分区：
文献类型：
--
作者：
Qian, Changgeng;Lai, Cheng-Jung;Voi, Maurizio
目的：考虑到组蛋白去乙酰化酶（HDAC）抑制剂可以诱导影响信号网络的多种表观遗传修饰，并与磷脂酰肌醇3-激酶（PI3K）抑制剂协同作用，我们开发了一种在癌细胞中同时抑制HDAC和PI3K的策略。实验设计：我们通过将HDAC抑制功能整合到PI3K抑制剂药效团中构建双作用抑制剂。CUDC-907是一种从这些双重抑制剂中选择的开发候选药物，我们对其进行了体外和体内评价，以确定其药理学特性、抗癌活性和作用机制。结果：CUDC-907有效抑制I类pi3k以及I类和II类HDAC酶。CUDC-907通过其整合的HDAC抑制活性，持续抑制PI3K-AKT-mTOR通路和补偿性信号分子，如RAF、MEK、MAPK、STAT-3，以及上游受体酪氨酸激酶。CUDC-907在培养和移植的癌细胞中均表现出比单靶点PI3K或HDAC抑制剂更强的生长抑制和促凋亡活性。结论：CUDC-907可能通过同时持续破坏多个致癌信号网络提供更好的治疗效果。临床癌症研究；18 (15);4104 - 13所示。AACR (C) 2012。
Purpose: Given that histone deacetylase (HDAC) inhibitors are known to induce multiple epigenetic modifications affecting signaling networks and act synergistically with phosphatidylinositol 3-kinase (PI3K) inhibitors, we developed a strategy to simultaneously inhibit HDACs and PI3K in cancer cells.Experimental Design: We constructed dual-acting inhibitors by incorporating HDAC inhibitory functionality into a PI3K inhibitor pharmacophore. CUDC-907, a development candidate selected from these dual inhibitors, was evaluated in vitro and in vivo to determine its pharmacologic properties, anticancer activity, and mechanism of action.Results: CUDC-907 potently inhibits class I PI3Ks as well as classes I and II HDAC enzymes. Through its integrated HDAC inhibitory activity, CUDC-907 durably inhibits the PI3K-AKT-mTOR pathway and compensatory signaling molecules such as RAF, MEK, MAPK, and STAT-3, as well as upstream receptor tyrosine kinases. CUDC-907 shows greater growth inhibition and proapoptotic activity than single-target PI3K or HDAC inhibitors in both cultured and implanted cancer cells.Conclusions: CUDC-907 may offer improved therapeutic benefits through simultaneous, sustained disruption of multiple oncogenic signaling networks. Clin Cancer Res; 18(15); 4104-13. (C)2012 AACR.