1. Identification of NVP-BKM120 as a Potent, Selective, Orally Bioavailable Class I PI3 Kinase Inhibitor for Treating Cancer
- Author
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Susan Kaufman, Zhang Yanchen, Joshua Haznedar, Daniel Menezes, Matthew Burger, Xiaohua Xin, Aaron Smith, Frazier Kelly, Sauveur-Michel Maira, Allan S. Wagman, Zhi-Jie Ni, Keith B. Pfister, Kay Huh, Isabel Zaror, Thomas Hendrickson, Joelle Verhagen, Gordana Atallah, Kevin Shoemaker, Bartulis Sarah, Michael Chin, Simon Ng, Kenneth Crawford, Dirksen E. Bussiere, Ed Iwanowicz, Mark Knapp, Isabelle Lee, Hanne Merritt, Marion Wiesmann, Charles Voliva, and Sabina Pecchi
- Subjects
Phosphoinositide 3-kinase ,biology ,business.industry ,Kinase ,Organic Chemistry ,Buparlisib ,Phases of clinical research ,Cancer ,Pharmacology ,medicine.disease ,Biochemistry ,chemistry.chemical_compound ,chemistry ,In vivo ,Drug Discovery ,biology.protein ,Medicine ,Signal transduction ,business ,PI3K/AKT/mTOR pathway - Abstract
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.
- Published
- 2011
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