In Vivo Efficacy of Natural Product-Inspired Irreversible Kinase Inhibitors
In Vivo Efficacy of Natural Product-Inspired Irreversible Kinase Inhibitors
复制标题
DOI：
10.1002/cbic.201000205
复制
发表时间：
2010-08-16
期刊：
影响因子：
3.2
通讯作者：
Winssinger, Nicolas
中科院分区：
文献类型：
--
作者：
Barluenga, Sofia;Jogireddy, Rajamalleswaramma;Winssinger, Nicolas
次霉素及其相关的含顺-烯酮基团的间苯二酸内酯(Ral)已成为替代杂环基序抑制蛋白激酶的药物载体，并被赋予了独特的选择性过滤器，其基础是与含有适当位置半胱氨酸残基的亲缘关系的一部分发生不可逆反应。在原位小鼠肾细胞癌(RECA)模型中，对两个典型的“编辑”的RAL进行了抗肿瘤、抗转移和抗血管生成效果的评估。这两个化合物(3和5)在体外都是很好的VEGFRs抑制剂，在体内抑制肿瘤生长的效果与FDA批准的VEGFRs抑制剂舒尼替尼相当，化合物3促进肺转移的程度与舒尼替尼相似，而化合物5强烈抑制肺转移。这项研究证实了不可逆激酶抑制剂的潜力和天然药效团的分子编辑，并对一个临床上重要的问题提供了令人鼓舞的结果。
Hypothemycin and related resorcylic acid lactones (RAL) bearing a cis-enone moiety have emerged as an alternative pharmacophore to heterocyclic motifs for kinase inhibition, and are endowed with a unique selectivity filter based on the irreversible reaction with a subset of the kinome bearing a suitably positioned cysteine residue. Two prototypical examples of "edited" RAL were evaluated for antitumoral, antimetastatic and antiangiogenic efficacy in an orthotopic murine renal cell carcinoma (RENCA) model. Both compounds (3 and 5) are good inhibitors of VEGFRs in vitro, and inhibited tumor growth in vivo with comparable efficacy to sunitinib, an FDA-approved VEGFRs inhibitor Compound 3 promoted lung metastasis to a similar extent as sunitinib, while compound 5 strongly inhibited lung metastasis. This study attests to the potential of irreversible kinase inhibitors and molecular editing of natural pharmacophores and provides encouraging results to a clinically significant problem