CC-223, a Potent and Selective Inhibitor of mTOR Kinase: In Vitro and In Vivo Characterization
CC-223, a Potent and Selective Inhibitor of mTOR Kinase: In Vitro and In Vivo Characterization
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DOI：
10.1158/1535-7163.mct-14-1052
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发表时间：
2015-06-01
影响因子：
5.7
通讯作者：
Raymon, Heather K.
中科院分区：
文献类型：
--
作者：
Mortensen, Deborah S.;Fultz, Kimberly E.;Raymon, Heather K.
MTOR是一种丝氨酸/苏氨酸激酶，调节细胞生长、新陈代谢、增殖和存活。MTOR复合体-1(MTORC1)和mTOR复合体-2(MTORC2)是PI3K-AKT通路的关键介质，在许多肿瘤中经常发生突变，导致mTOR信号的过度激活。虽然雷帕霉素类似物，变构抑制剂，只针对mTORC1复合体，已经显示出一些临床活性，但假设mTOR激酶抑制剂，阻断mTORC1和mTORC2信号，将扩大治疗潜力。在这里，我们描述了CC-223的临床前特征。CC-223是一种有效的、选择性的、口服生物可用的mTOR激酶抑制剂，在细胞系统中显示出对mTORC1(pS6RP和p4EBP1)和mTORC2[pakt(S473)]的抑制作用。在血液和实体瘤细胞系中表现出生长抑制活性。与雷帕霉素相比，CC-223在细胞内抑制mTOR激酶可更彻底地抑制mTOR途径的生物标志物，并提高其抗增殖活性。在一组血液肿瘤细胞系中显示出生长抑制活性和细胞凋亡。相关分析表明，IRF4的表达水平与耐药有关，而mTOR通路的激活似乎与敏感性有关。单次口服CC-223治疗后，荷瘤小鼠体内肿瘤生物标志物受到抑制。CC-223在多个实体瘤移植瘤中表现出剂量依赖性的肿瘤生长抑制。CC-223对mTOR通路标记物pS6RP和PACT的显著抑制表明，CC-223的抗肿瘤活性是通过抑制mTORC1和mTORC2实现的。CC-223目前处于I期临床试验。(C)2015年AACR。
mTOR is a serine/threonine kinase that regulates cell growth, metabolism, proliferation, and survival. mTOR complex-1 (mTORC1) and mTOR complex-2 (mTORC2) are critical mediators of the PI3K-AKT pathway, which is frequently mutated in many cancers, leading to hyperactivation of mTOR signaling. Although rapamycin analogues, allosteric inhibitors that target only the mTORC1 complex, have shown some clinical activity, it is hypothesized that mTOR kinase inhibitors, blocking both mTORC1 and mTORC2 signaling, will have expanded therapeutic potential. Here, we describe the preclinical characterization of CC-223. CC-223 is a potent, selective, and orally bioavailable inhibitor of mTOR kinase, demonstrating inhibition of mTORC1 (pS6RP and p4EBP1) and mTORC2 [pAKT(S473)] in cellular systems. Growth inhibitory activity was demonstrated in hematologic and solid tumor cell lines. mTORkinase inhibition in cells, by CC-223, resulted in more complete inhibition of the mTOR pathway biomarkers and improved antiproliferative activity as compared with rapamycin. Growth inhibitory activity and apoptosis was demonstrated in a panel of hematologic cancer cell lines. Correlative analysis revealed that IRF4 expression level associates with resistance, whereas mTOR pathway activation seems to associate with sensitivity. Treatment with CC-223 afforded in vivo tumor biomarker inhibition in tumor-bearing mice, after a single oral dose. CC-223 exhibited dose-dependent tumor growth inhibition in multiple solid tumor xenografts. Significant inhibition of mTOR pathway markers pS6RP and pAKT in CC-223-treated tumors suggests that the observed antitumor activity of CC-223 was mediated through inhibition of both mTORC1 and mTORC2. CC-223 is currently in phase I clinical trials. (C) 2015 AACR.