Identification of NVP-BKM120 as a Potent, Selective, Orally Bioavailable Class I PI3 Kinase Inhibitor for Treating Cancer
Identification of NVP-BKM120 as a Potent, Selective, Orally Bioavailable Class I PI3 Kinase Inhibitor for Treating Cancer
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DOI：
10.1021/ml200156t
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发表时间：
2011-10-01
影响因子：
4.2
通讯作者：
Voliva, Charles F.
中科院分区：
文献类型：
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作者：
Burger, Matthew T.;Pecchi, Sabina;Voliva, Charles F.
磷酸肌苷-3激酶（pi3k）是重要的肿瘤靶点，因为在多种人类癌症中这一信号通路的解除管制。本文以结构为导向对一系列2-morpholino， 4-取代，6-杂环吡啶进行了优化，通过调节6位杂环的电子学来改善其药动学性质，并通过修饰4位取代基进一步调整其整体药物性质。由此得到的2,4-二morpholino 6-杂环吡啶是有效的I类PI3K抑制剂，在PI3K依赖的细胞系中具有机制调节作用，并且在PI3K通路失调的肿瘤异种移植模型（A2780卵巢和U87MG胶质瘤）中具有体内疗效。这些努力最终导致了15 （NVP-BKM120）的发现，目前正在进行II期临床试验，用于治疗癌症。
Phosphoinositide-3-kinases (PI3Ks) are important oncology targets due to the deregulation of this signaling pathway in a wide variety of human cancers. Herein we describe the structure guided optimization of a series of 2-morpholino, 4-substituted, 6-heterocydic pyrirnidines where the pharmacokinetic properties were improved by modulating the electronics of the 6-position heterocycle, and the overall druglike properties were fine-tuned further by modification of the 4-position substituent. The resulting 2,4-bismorpholino 6-heterocyclic pyrirnidines are potent class I PI3K inhibitors showing mechanism modulation in PI3K dependent cell lines and in vivo efficacy in tumor xenograft models with PI3K pathway deregulation (A2780 ovarian and U87MG glioma). These efforts culminated in the discovery of 15 (NVP-BKM120), currently in Phase II clinical trials for the treatment of cancer.