title: Synthesis and in Vitro and in Vivo Evaluation of Phosphoinositide-3-kinase Inhibitors.
abstract: Phospoinositide-3-kinases (PI3K) are important oncology targets due to the deregulation of this signaling pathway in a wide variety of human cancers. A series of 2-morpholino, 4-substituted, 6-(3-hydroxyphenyl) pyrimidines have been reported as potent inhibitors of PI3Ks. Herein, we describe the structure-guided optimization of these pyrimidines with a focus on replacing the phenol moiety, while maintaining potent target inhibition and improving in vivo properties. A series of 2-morpholino, 4-substituted, 6-heterocyclic pyrimidines, which potently inhibit PI3K, were discovered. Within this series a compound, 17, was identified with suitable pharmacokinetic (PK) properties, which allowed for the establishment of a PI3K PK/pharmacodynamic-efficacy relationship as determined by in vivo inhibition of AKT(Ser473) phosphorylation and tumor growth inhibition in a mouse A2780 tumor xenograft model.
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: 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: 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: 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: 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: 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: 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: 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: 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: 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: Hanne
authors.initials: H
authors.lastname: Merrit
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: Weismann
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: 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: Charles F
authors.initials: CF
authors.lastname: Voliva
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: Sabina
authors.initials: S
authors.lastname: Pecchi
keywords: PI3K/AKT pathway; phosphoinositide 3-kinase alpha