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

2011; American Chemical Society; Volume: 2; Issue: 10 Linguagem: Inglês

10.1021/ml200156t

1948-5875

Matthew T. Burger, Sabina Pecchi, Allan S. Wagman, Zhi‐Jie Ni, Mark Knapp, Thomas F. Hendrickson, Gordana Atallah, Keith Pfister, Yanchen Zhang, Sarah Bartulis, Kelly Frazier, Simon S.M. Ng, Aaron Smith, Joelle Verhagen, Joshua Haznedar, Kay Huh, Ed Iwanowicz, Xiaohua Xin, Daniel L. Menezes, Hanne Merritt, Isabelle Lee, Marion Wiesmann, Susan Kaufman, Kenneth Crawford, Michael T. Chin, Dirksen E. Bussiere, Kevin Shoemaker, Isabel Zaror, Sauveur-Michel Maira, Charles F. Voliva,

Chronic Lymphocytic Leukemia Research

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.