title: Identification of NVP-BKM120 as a Potent, Selective, Orally Bioavailable Class I PI3 Kinase Inhibitor for Treating Cancer.
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.
authors.affiliation: Global Discovery Chemistry/Oncology & Exploratory Chemistry, Novartis Institutes for Biomedical Research , 4560 Horton Street, Emeryville, California 94608, United States.
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Burger
authors.affiliation: Global Discovery Chemistry/Oncology & Exploratory Chemistry, Novartis Institutes for Biomedical Research , 4560 Horton Street, Emeryville, California 94608, United States.
authors.forename: Sabina
authors.initials: S
authors.lastname: Pecchi
authors.affiliation: Global Discovery Chemistry/Oncology & Exploratory Chemistry, Novartis Institutes for Biomedical Research , 4560 Horton Street, Emeryville, California 94608, United States.
authors.forename: Allan
authors.initials: A
authors.lastname: Wagman
authors.affiliation: Global Discovery Chemistry/Oncology & Exploratory Chemistry, Novartis Institutes for Biomedical Research , 4560 Horton Street, Emeryville, California 94608, United States.
authors.forename: Zhi-Jie
authors.initials: ZJ
authors.lastname: Ni
authors.affiliation: Global Discovery Chemistry/Oncology & Exploratory Chemistry, Novartis Institutes for Biomedical Research , 4560 Horton Street, Emeryville, California 94608, United States.
authors.forename: Mark
authors.initials: M
authors.lastname: Knapp
authors.affiliation: Global Discovery Chemistry/Oncology & Exploratory Chemistry, Novartis Institutes for Biomedical Research , 4560 Horton Street, Emeryville, California 94608, United States.
authors.forename: Thomas
authors.initials: T
authors.lastname: Hendrickson
authors.affiliation: Global Discovery Chemistry/Oncology & Exploratory Chemistry, Novartis Institutes for Biomedical Research , 4560 Horton Street, Emeryville, California 94608, United States.
authors.forename: Gordana
authors.initials: G
authors.lastname: Atallah
authors.affiliation: Global Discovery Chemistry/Oncology & Exploratory Chemistry, Novartis Institutes for Biomedical Research , 4560 Horton Street, Emeryville, California 94608, United States.
authors.forename: Keith
authors.initials: K
authors.lastname: Pfister
authors.affiliation: Global Discovery Chemistry/Oncology & Exploratory Chemistry, Novartis Institutes for Biomedical Research , 4560 Horton Street, Emeryville, California 94608, United States.
authors.forename: Yanchen
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Global Discovery Chemistry/Oncology & Exploratory Chemistry, Novartis Institutes for Biomedical Research , 4560 Horton Street, Emeryville, California 94608, United States.
authors.forename: Sarah
authors.initials: S
authors.lastname: Bartulis
authors.affiliation: Global Discovery Chemistry/Oncology & Exploratory Chemistry, Novartis Institutes for Biomedical Research , 4560 Horton Street, Emeryville, California 94608, United States.
authors.forename: Kelly
authors.initials: K
authors.lastname: Frazier
authors.affiliation: Global Discovery Chemistry/Oncology & Exploratory Chemistry, Novartis Institutes for Biomedical Research , 4560 Horton Street, Emeryville, California 94608, United States.
authors.forename: Simon
authors.initials: S
authors.lastname: Ng
authors.affiliation: Global Discovery Chemistry/Oncology & Exploratory Chemistry, Novartis Institutes for Biomedical Research , 4560 Horton Street, Emeryville, California 94608, United States.
authors.forename: Aaron
authors.initials: A
authors.lastname: Smith
authors.affiliation: Global Discovery Chemistry/Oncology & Exploratory Chemistry, Novartis Institutes for Biomedical Research , 4560 Horton Street, Emeryville, California 94608, United States.
authors.forename: Joelle
authors.initials: J
authors.lastname: Verhagen
authors.affiliation: Global Discovery Chemistry/Oncology & Exploratory Chemistry, Novartis Institutes for Biomedical Research , 4560 Horton Street, Emeryville, California 94608, United States.
authors.forename: Joshua
authors.initials: J
authors.lastname: Haznedar
authors.affiliation: Global Discovery Chemistry/Oncology & Exploratory Chemistry, Novartis Institutes for Biomedical Research , 4560 Horton Street, Emeryville, California 94608, United States.
authors.forename: Kay
authors.initials: K
authors.lastname: Huh
authors.affiliation: Global Discovery Chemistry/Oncology & Exploratory Chemistry, Novartis Institutes for Biomedical Research , 4560 Horton Street, Emeryville, California 94608, United States.
authors.forename: Ed
authors.initials: E
authors.lastname: Iwanowicz
authors.affiliation: Global Discovery Chemistry/Oncology & Exploratory Chemistry, Novartis Institutes for Biomedical Research , 4560 Horton Street, Emeryville, California 94608, United States.
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Xin
authors.affiliation: Global Discovery Chemistry/Oncology & Exploratory Chemistry, Novartis Institutes for Biomedical Research , 4560 Horton Street, Emeryville, California 94608, United States.
authors.forename: Daniel
authors.initials: D
authors.lastname: Menezes
authors.affiliation: Global Discovery Chemistry/Oncology & Exploratory Chemistry, Novartis Institutes for Biomedical Research , 4560 Horton Street, Emeryville, California 94608, United States.
authors.forename: Hanne
authors.initials: H
authors.lastname: Merritt
authors.affiliation: Global Discovery Chemistry/Oncology & Exploratory Chemistry, Novartis Institutes for Biomedical Research , 4560 Horton Street, Emeryville, California 94608, United States.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Lee
authors.affiliation: Global Discovery Chemistry/Oncology & Exploratory Chemistry, Novartis Institutes for Biomedical Research , 4560 Horton Street, Emeryville, California 94608, United States.
authors.forename: Marion
authors.initials: M
authors.lastname: Wiesmann
authors.affiliation: Global Discovery Chemistry/Oncology & Exploratory Chemistry, Novartis Institutes for Biomedical Research , 4560 Horton Street, Emeryville, California 94608, United States.
authors.forename: Susan
authors.initials: S
authors.lastname: Kaufman
authors.affiliation: Global Discovery Chemistry/Oncology & Exploratory Chemistry, Novartis Institutes for Biomedical Research , 4560 Horton Street, Emeryville, California 94608, United States.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Crawford
authors.affiliation: Global Discovery Chemistry/Oncology & Exploratory Chemistry, Novartis Institutes for Biomedical Research , 4560 Horton Street, Emeryville, California 94608, United States.
authors.forename: Michael
authors.initials: M
authors.lastname: Chin
authors.affiliation: Global Discovery Chemistry/Oncology & Exploratory Chemistry, Novartis Institutes for Biomedical Research , 4560 Horton Street, Emeryville, California 94608, United States.
authors.forename: Dirksen
authors.initials: D
authors.lastname: Bussiere
authors.affiliation: Global Discovery Chemistry/Oncology & Exploratory Chemistry, Novartis Institutes for Biomedical Research , 4560 Horton Street, Emeryville, California 94608, United States.
authors.forename: Kevin
authors.initials: K
authors.lastname: Shoemaker
authors.affiliation: Global Discovery Chemistry/Oncology & Exploratory Chemistry, Novartis Institutes for Biomedical Research , 4560 Horton Street, Emeryville, California 94608, United States.
authors.forename: Isabel
authors.initials: I
authors.lastname: Zaror
authors.affiliation: Global Discovery Chemistry/Oncology & Exploratory Chemistry, Novartis Institutes for Biomedical Research , 4560 Horton Street, Emeryville, California 94608, United States.
authors.forename: Sauveur-Michel
authors.initials: SM
authors.lastname: Maira
authors.affiliation: Global Discovery Chemistry/Oncology & Exploratory Chemistry, Novartis Institutes for Biomedical Research , 4560 Horton Street, Emeryville, California 94608, United States.
authors.forename: Charles F
authors.initials: CF
authors.lastname: Voliva
keywords: NVP-BKM120; PI3K/AKT3 pathway; phosphoinositide-3-kinase