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ACS Med Chem Lett. 2011 Aug 26;2(10):774-9. doi: 10.1021/ml200156t. eCollection 2011 Oct 13.

Identification of NVP-BKM120 as a Potent, Selective, Orally Bioavailable Class I PI3 Kinase Inhibitor for Treating Cancer.

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Global Discovery Chemistry/Oncology & Exploratory Chemistry, Novartis Institutes for Biomedical Research , 4560 Horton Street, Emeryville, California 94608, United States.


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-heterocyclic pyrimidines 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 pyrimidines 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.


NVP-BKM120; PI3K/AKT3 pathway; phosphoinositide-3-kinase

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