Preclinical Characterization of OSI-027, a Potent and Selective Inhibitor of mTORC1 and mTORC2: Distinct from Rapamycin
Preclinical Characterization of OSI-027, a Potent and Selective Inhibitor of mTORC1 and mTORC2: Distinct from Rapamycin
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DOI：
10.1158/1535-7163.mct-10-1099
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发表时间：
2011-08-01
影响因子：
5.7
通讯作者：
Pachter, Jonathan A.
中科院分区：
文献类型：
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作者：
Bhagwat, Shripad V.;Gokhale, Prafulla C.;Pachter, Jonathan A.
磷酸肌肽3-激酶(PI3K)/AKT/mTOR通路在人类癌症中经常被激活，mTOR是临床验证的靶点。mTOR形成两种不同的多蛋白复合物，mTORC1和mTORC2，它们调节细胞生长、代谢、增殖和存活。雷帕霉素及其类似物通过与mTORC1的变构结合部分抑制mTOR，而不是mTORC2，并且在某些癌症中显示出临床效用。在这里，我们报告了osii -027的临床前特征，这是一种选择性和有效的mTORC1和mTORC2双重抑制剂，其生化IC50值分别为22 nmol/L和65 nmol/L。相对于PI3K α、PI3K β、PI3K γ和DNA-PK， OSI-027对mTOR的选择性超过100倍。在体内和体外多种癌症模型中，OSI-027抑制mTORC1底物4E-BP1和S6K1以及mTORC2底物AKT的磷酸化。osio -027和OXA-01 （osio -027的类似物）能有效抑制几种雷帕霉素敏感和不敏感的非工程和工程癌细胞系的增殖，并诱导PI3K-AKT信号激活的肿瘤细胞系的细胞死亡。OSI-027对肿瘤组织中4E-BP1和AKT的磷酸化具有浓度依赖性的药效学作用，从而抑制肿瘤生长。OSI-027在代表不同组织学的几种不同的人类异种移植物模型中显示出强大的抗肿瘤活性。此外，在COLO 205和GEO结肠癌异种移植模型中，与雷帕霉素相比，OSI-027的疗效更佳。我们的研究结果进一步支持了mTOR作为肿瘤生长驱动因子的重要作用，并确定了OSI-027是一种有效的抗癌药物。OSI-027目前正在癌症患者的I期临床试验中。巨蟹座；10 (8);1394 - 406。(c) 2011年aacr。
The phosphoinositide 3-kinase (PI3K)/AKT/mTOR pathway is frequently activated in human cancers, and mTOR is a clinically validated target. mTOR forms two distinct multiprotein complexes, mTORC1 and mTORC2, which regulate cell growth, metabolism, proliferation, and survival. Rapamycin and its analogues partially inhibit mTOR through allosteric binding to mTORC1, but not mTORC2, and have shown clinical utility in certain cancers. Here, we report the preclinical characterization of OSI-027, a selective and potent dual inhibitor of mTORC1 and mTORC2 with biochemical IC50 values of 22 nmol/L and 65 nmol/L, respectively. OSI-027 shows more than 100-fold selectivity for mTOR relative to PI3K alpha, PI3K beta, PI3K gamma, and DNA-PK. OSI-027 inhibits phosphorylation of the mTORC1 substrates 4E-BP1 and S6K1 as well as the mTORC2 substrate AKT in diverse cancer models in vitro and in vivo. OSI-027 and OXA-01 (close analogue of OSI-027) potently inhibit proliferation of several rapamycin-sensitive and -insensitive nonengineered and engineered cancer cell lines and also, induce cell death in tumor cell lines with activated PI3K-AKT signaling. OSI-027 shows concentration-dependent pharmacodynamic effects on phosphorylation of 4E-BP1 and AKT in tumor tissue with resulting tumor growth inhibition. OSI-027 shows robust antitumor activity in several different human xenograft models representing various histologies. Furthermore, in COLO 205 and GEO colon cancer xenograft models, OSI-027 shows superior efficacy compared with rapamycin. Our results further support the important role of mTOR as a driver of tumor growth and establish OSI-027 as a potent anticancer agent. OSI-027 is currently in phase I clinical trials in cancer patients. Mol Cancer Ther; 10(8); 1394-406. (C) 2011 AACR.