Preclinical profile of a potent gamma-secretase inhibitor targeting notch signaling with in vivo efficacy and pharmacodynamic properties.
Preclinical profile of a potent gamma-secretase inhibitor targeting notch signaling with in vivo efficacy and pharmacodynamic properties.
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具有体内功效和药效特性的有效γ-分泌酶抑制剂靶向Notch信号的临床前谱。
DOI：
10.1158/0008-5472.can-09-1843
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发表时间：
2009-10-01
期刊：
影响因子：
11.2
通讯作者：
Boylan JF
中科院分区：
文献类型：
--
作者：
Luistro L;He W;Smith M;Packman K;Vilenchik M;Carvajal D;Roberts J;Cai J;Berkofsky-Fessler W;Hilton H;Linn M;Flohr A;Jakob-Røtne R;Jacobsen H;Glenn K;Heimbrook D;Boylan JF
Notch信号是肿瘤学中非常感兴趣的领域。RO 4929097是一种有效的选择性γ-分泌酶抑制剂，在肿瘤细胞中产生Notch信号传导抑制活性。在无细胞和细胞试验中，RO 4929097 IC 50处于低纳摩尔范围内，对75种其他各种类型的蛋白质（受体、离子通道和酶）具有>100倍的选择性。RO 4929097抑制肿瘤细胞中的Notch加工，通过Western印迹法测定细胞内Notch表达的减少。这导致Notch转录靶基因Hes 1的表达降低。RO 4929097不会阻断肿瘤细胞增殖或诱导细胞凋亡，而是产生转化较少、扁平、生长较慢的表型。口服给药后，RO 4929097具有活性。在不存在体重减轻或Notch相关毒性的情况下，在间歇或每日时间表测试的8个异种移植物中的7个中显示出抗肿瘤活性。重要的是，在终止给药后维持疗效。血管生成逆转录-PCR阵列数据显示几个关键的血管生成基因的表达减少。此外，比较微阵列分析表明肿瘤细胞分化是一种额外的作用模式。这些临床前结果支持在使用间歇给药方案的临床研究中评价RO 4929097。一项多中心I期肿瘤剂量递增研究正在进行中。
Notch signaling is an area of great interest in oncology. RO4929097 is a potent and selective inhibitor of γ-secretase, producing inhibitory activity of Notch signaling in tumor cells. The RO4929097 IC50 in cell-free and cellular assays is in the low nanomolar range with >100-fold selectivity with respect to 75 other proteins of various types (receptors, ion channels, and enzymes). RO4929097 inhibits Notch processing in tumor cells as measured by the reduction of intracellular Notch expression by Western blot. This leads to reduced expression of the Notch transcriptional target gene Hes1. RO4929097 does not block tumor cell proliferation or induce apoptosis but instead produces a less transformed, flattened, slower-growing phenotype. RO4929097 is active following oral dosing. Antitumor activity was shown in 7 of 8 xenografts tested on an intermittent or daily schedule in the absence of body weight loss or Notch-related toxicities. Importantly, efficacy is maintained after dosing is terminated. Angiogenesis reverse transcription-PCR array data show reduced expression of several key angiogenic genes. In addition, comparative microarray analysis suggests tumor cell differentiation as an additional mode of action. These preclinical results support evaluation of RO4929097 in clinical studies using an intermittent dosing schedule. A multicenter phase I dose escalation study in oncology is under way.