OSI-930: A novel selective inhibitor of Kit and kinase insert domain receptor tyrosine kinases with antitumor activity in mouse xenograft models
OSI-930: A novel selective inhibitor of Kit and kinase insert domain receptor tyrosine kinases with antitumor activity in mouse xenograft models
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DOI：
10.1158/0008-5472.can-05-2873
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发表时间：
2006-01-15
期刊：
影响因子：
11.2
通讯作者：
Gibson, NW
中科院分区：
文献类型：
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作者：
Garton, AJ;Crew, APA;Gibson, NW
OSI-930是酪氨酸激酶受体Kit和激酶插入结构域受体（KDR）的新型抑制剂，目前正在临床研究中进行评估。OSI-930在完整细胞中以相似的效力选择性抑制Kit和KDR，并且在口服给药后也抑制这些靶点。我们研究了体外细胞实验中观察到的效力、口服给药后的血浆暴露水平、体内靶抑制的时间过程和肿瘤异种移植模型中OSI-930的抗肿瘤活性之间的关系。在表达HMC-1的突变Kit异种移植物模型中，口服剂量在10 - 50 mg/kg之间可以实现Kit的长期抑制，并且该剂量范围与抗肿瘤活性相关。同样，野生型Kit在NCI-11526异种移植模型中的长期抑制作用在口服剂量为100至200 mg/kg时被观察到，该剂量水平在该模型以及大多数其他异种移植模型中具有显著的抗肿瘤活性。数据表明，在小鼠异种移植物模型中，观察到osii -930的抗肿瘤活性，剂量水平可以长期维持对osii -930分子靶点的显著抑制。此外，在这些有效剂量水平下，对osii -930的血浆暴露水平进行药代动力学评估，提供了可能需要的目标血浆浓度的估计，以实现对人体内Kit和KDR的长期抑制，因此有望在未来的osii -930临床评估中产生治疗益处。
OSI-930 is a novel inhibitor of the receptor tyrosine kinases Kit and kinase insert domain receptor (KDR), which is currently being evaluated in clinical studies. OSI-930 selectively inhibits Kit and KDR with similar potency in intact cells and also inhibits these targets in vivo following oral dosing. We have investigated the relationships between the potency observed in cell-based assays in vitro, the plasma exposure levels achieved following oral dosing, the time course of target inhibition in vivo, and antitumor activity of OSI-930 in tumor xenograft models. In the mutant Kit-expressing HMC-1 xenograft model, prolonged inhibition of Kit was achieved at oral doses between 10 and 50 mg/kg and this dose range was associated with antitumor activity. Similarly, prolonged inhibition of wild-type Kit in the NCI-11526 xenograft model was observed at oral doses of 100 to 200 mg/kg, which was the dose level associated with significant antitumor activity in this model as well as in the majority of other xenograft models tested. The data suggest that antitumor activity of OSI-930 in mouse xenograft models is observed at dose levels that maintain a significant level of inhibition of the molecular targets of OSI-930 for a prolonged period. Furthermore, pharmacokinetic evaluation of the plasma exposure levels of OSI-930 at these effective dose levels provides an estimate of the target plasma concentrations that may be required to achieve prolonged inhibition of Kit and KDR in humans and which would therefore be expected to yield a therapeutic benefit in future clinical evaluations of OSI-930.