2. Academic Validation
  3. Synthesis and in Vitro and in Vivo Evaluation of Phosphoinositide-3-kinase Inhibitors

Synthesis and in Vitro and in Vivo Evaluation of Phosphoinositide-3-kinase Inhibitors

  • ACS Med Chem Lett. 2010 Oct 13;2(1):34-8. doi: 10.1021/ml1001932.
Matthew T Burger 1,  Mark Knapp 1,  Allan Wagman 1,  Zhi-Jie Ni 1,  Thomas Hendrickson 1,  Gordana Atallah 1,  Yanchen Zhang 1,  Kelly Frazier 1,  Joelle Verhagen 1,  Keith Pfister 1,  Simon Ng 1,  Aaron Smith 1,  Sarah Bartulis 1,  Hanne Merrit 1,  Marion Weismann 1,  Xiaohua Xin 1,  Joshua Haznedar 1,  Charles F Voliva 1,  Ed Iwanowicz 1,  Sabina Pecchi 1
Affiliations

Affiliation

  • 1 Global Discovery Chemistry/Oncology & Exploratory Chemistry, Novartis Institutes for Biomedical Research, 4560 Horton Street, Emeryville, California 94608, United States.
PMID: 24900252 DOI: 10.1021/ml1001932
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.

Keywords

PI3K/AKT pathway; phosphoinositide 3-kinase alpha.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-18310
    PI3K Inhibitor