Structure-based design of thienobenzoxepin inhibitors of PI3-kinase

Steven T Staben; Michael Siu; Richard Goldsmith; Alan G Olivero; Steven Do; Daniel J Burdick; Timothy P Heffron; Jenna Dotson; Daniel P Sutherlin; Bing-Yan Zhu; Vickie Tsui; Hoa Le; Leslie Lee; John Lesnick; Cristina Lewis; Jeremy M Murray; Jim Nonomiya; Jodie Pang; Wei Wei Prior; Laurent Salphati; Lionel Rouge; Deepak Sampath; Steve Sideris; Christian Wiesmann; Ping Wu

doi:10.1016/j.bmcl.2011.04.124

Structure-based design of thienobenzoxepin inhibitors of PI3-kinase

Bioorg Med Chem Lett. 2011 Jul 1;21(13):4054-8. doi: 10.1016/j.bmcl.2011.04.124. Epub 2011 May 13.

Affiliation

¹ Discovery Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA. stevents@gene.com

PMID: 21636270
DOI: 10.1016/j.bmcl.2011.04.124

Abstract

Starting from thienobenzopyran HTS hit 1, co-crystallization, molecular modeling and metabolic analysis were used to design potent and metabolically stable inhibitors of PI3-kinase. Compound 15 demonstrated PI3K pathway suppression in a mouse MCF7 xenograft model.

MeSH terms

Animals
Benzoxepins / chemical synthesis*
Benzoxepins / chemistry
Benzoxepins / pharmacology
Cell Line, Tumor
Crystallography, X-Ray
Drug Design*
Enzyme Activation / drug effects
Enzyme Inhibitors / chemical synthesis*
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology
Humans
Inhibitory Concentration 50
Mice
Molecular Structure
Phosphoinositide-3 Kinase Inhibitors*
Structure-Activity Relationship
Thiophenes / chemical synthesis*
Thiophenes / chemistry
Thiophenes / pharmacology
Xenograft Model Antitumor Assays

Substances

Benzoxepins
Enzyme Inhibitors
Phosphoinositide-3 Kinase Inhibitors
Thiophenes