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首页> 外文期刊>Cancer research: The official organ of the American Association for Cancer Research, Inc >Preclinical profile of a potent gamma-secretase inhibitor targeting notch signaling with in vivo efficacy and pharmacodynamic properties.
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Preclinical profile of a potent gamma-secretase inhibitor targeting notch signaling with in vivo efficacy and pharmacodynamic properties.

机译：靶向缺口信号的有效γ-分泌酶抑制剂的临床前概况，具有体内功效和药效学性质。

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摘要

Notch signaling is an area of great interest in oncology. RO4929097 is a potent and selective inhibitor of gamma-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.
机译：陷波信号传导是肿瘤学领域中非常令人感兴趣的领域。 RO4929097是有效且选择性的γ-分泌酶抑制剂，可在肿瘤细胞中产生Notch信号传导的抑制活性。在无细胞和细胞测定中，RO4929097 IC50处于低纳摩尔范围内，相对于75种其他各种类型的蛋白质（受体，离子通道和酶），其选择性> 100倍。 RO4929097抑制肿瘤细胞中的Notch加工，这是通过Western blot检测到细胞内Notch表达的降低来衡量的。这导致Notch转录靶基因Hes1的表达降低。 RO4929097不会阻止肿瘤细胞增殖或诱导细胞凋亡，而是会产生较少转化，变平，生长缓慢的表型。口服给药后，RO4929097具有活性。在没有体重减轻或Notch相关毒性的情况下，以间歇或每日时间表测试的8种异种移植物中有7种显示出抗肿瘤活性。重要的是，给药终止后仍保持功效。血管生成逆转录-PCR阵列数据显示几种关键血管生成基因的表达降低。另外，比较性微阵列分析表明肿瘤细胞分化是另一种作用方式。这些临床前结果支持使用间歇给药方案在临床研究中评估RO4929097。一项正在进行的肿瘤多中心I期剂量递增研究正在进行中。

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