Burger, Matthew, Pecchi, Sabina, Wagman, Allan, Ni, Zhijie, Knapp, Mark, Hendrickson, Thomas, Atallah, Gordana, Pfister, Keith, Zhang, Yanchen, Bartulis, Sarah, Ng, Simon, Verhagen, Joelle, Huh, Kay, Iwanowicz, Edwin, Menezes, Daniel, Merritt, Hanne, Lee, Isabelle, Weismann, Marion, Kaufman, Susan, Crawford, Kenneth, Chin, Michael, Bussiere, Dirksen, Shoemaker, Kevin, Verhagen, Joelle, Frazier, Kelly, Xin, Xiaohua, Haznedar, Joshua, Zaror, Isabel, Maira, Sauveur-Michel and Voliva, Charles (2011) Identification of NVP-BKM120 as a Potent, Selective, Orally Bioavailable Class I PI3 Kinase Inhibitor for Treating Cancer. ACS Medicinal Chemistry Letters, 2 (10). pp. 774-779. ISSN 1948-5875

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.

Item Type:	Article
Keywords:	NVP-BKM120, PI3 Kinase Inhibitor
Date Deposited:	13 Oct 2015 13:15
Last Modified:	13 Oct 2015 13:15
URI:	https://oak.novartis.com/id/eprint/5162