Initial testing (stage 1) of the Akt inhibitor GSK690693 by the pediatric preclinical testing program.
Initial testing (stage 1) of the Akt inhibitor GSK690693 by the pediatric preclinical testing program.
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DOI：
10.1002/pbc.22710
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发表时间：
2010-12-15
影响因子：
3.2
通讯作者：
Lock, Richard B.
中科院分区：
文献类型：
--
作者：
Carol, Hernan;Morton, Christopher L.;Gorlick, Richard;Kolb, E. Anders;Keir, Stephen T.;Reynolds, C. Patrick;Kang, Min H.;Maris, John M.;Billups, Catherine;Smith, Malcolm A.;Houghton, Peter J.;Lock, Richard B.
GSK690693是促生存蛋白激酶Akt的小分子ATP竞争性抑制物。由于Akt调节多个下游靶点，包括转录因子、糖原合成酶3、促凋亡蛋白Bad以及MDM2和mTORC1，因此它被与儿科临床前测试计划(PPTP)的体外和体内小组进行了测试。GSK690693在1~10μM的浓度范围内进行体外试验，并以30 mg/kg/d×5的剂量连续6周与体内移植瘤对照。使用了三种体内抗肿瘤活性的测量：1)模拟临床环境的客观反应测量；2)治疗到对照(T/C)肿瘤体积测量；以及3)基于每种异种移植的处理动物和对照动物的中位无事件生存(EFS)的事件发生时间测量。GSK690693在体外抑制细胞生长，IC50值在6.5nM~10μM之间。在体内，GSK690693显著增加了34个实体瘤移植瘤中的11个(32%)的EFS，尤其是在所有6个骨肉瘤模型中最明显，但在所测试的8个ALL异种移植瘤中没有。没有观察到客观反应，只有一个实体瘤符合EFS T/C中间活性标准。GSK690693在体外表现出广泛的活性，但我们对实体瘤和体内所有PPTP的结果表明，作为单一药物，在所使用的剂量和程序下，GSK690693仅具有适度的抗肿瘤活性。
GSK690693 is a small molecule ATP-competitive inhibitor of the pro-survival kinase Akt. Since Akt regulates multiple downstream targets including transcription factors, glycogen synthase 3, the pro-apoptotic protein Bad, as well as MDM2 and mTORC1, it was tested against the in vitro and in vivo panels of the Pediatric Preclinical Testing Program (PPTP). GSK690693 was tested in vitro at concentrations from 1 nM to 10 μM, and against the in vivo panel of xenografts at a dose of 30 mg/kg daily x 5 for 6 consecutive weeks. Three measures of in vivo antitumor activity were used: 1) an objective response measure modeled after the clinical setting; 2) a treated to control (T/C) tumor volume measure; and 3) a time to event measure based on the median event-free survival (EFS) of treated and control animals for each xenograft. GSK690693 inhibited cell growth in vitro with IC50 values between 6.5 nM and >10 μM. In vivo, GSK690693 significantly increased EFS in 11 of 34 (32%) solid tumor xenografts, most notably in all 6 osteosarcoma models, but not in any of the 8 ALL xenografts tested. No objective responses were observed and only one solid tumor met EFS T/C criteria for intermediate activity. GSK690693 demonstrated broad activity in vitro, however our results against both the solid tumor and ALL PPTP in vivo panels demonstrate that, as single agent at the dose and schedule used, GSK690693 has only modest antitumor activity.
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影响因子：
20.3
作者：
Levy, Dana S.;Kahana, Jason A.;Kumar, Rakesh
通讯作者：
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影响因子：
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作者：
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影响因子：
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作者：
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DOI：
10.1158/1078-0432.ccr-09-1026
发表时间：
2010-01-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
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作者：
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通讯作者：
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影响因子：
11.5
作者：
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通讯作者：
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