Bioorganic & medicinal chemistry letters, 2013-05, Vol.23 (9), p.2606-2613
- Staben, Steven T.
- Ndubaku, Chudi
- Blaquiere, Nicole
- Belvin, Marcia
- Bull, Richard J.
- Dudley, Danette
- Edgar, Kyle
- Gray, Daniel
- Heald, Robert
- Heffron, Timothy P.
- Jones, Graham E.
- Jones, Mark
- Kolesnikov, Aleks
- Lee, Leslie
- Lesnick, John
- Lewis, Cristina
- Murray, Jeremy
- McLean, Neville J.
- Nonomiya, Jim
- Olivero, Alan G.
- Ord, Rachel
- Pang, Jodie
- Price, Stephen
- Prior, Wei Wei
- Rouge, Lionel
- Salphati, Laurent
- Sampath, Deepak
- Wallin, Jeff
- Wang, Lan
- Wei, BinQing
- Weismann, Christian
- Wu, Ping
2013
Volltextzugriff (PDF)
Details
- Autor(en) / Beteiligte
- Staben, Steven T.
- Ndubaku, Chudi
- Blaquiere, Nicole
- Belvin, Marcia
- Bull, Richard J.
- Dudley, Danette
- Edgar, Kyle
- Gray, Daniel
- Heald, Robert
- Heffron, Timothy P.
- Jones, Graham E.
- Jones, Mark
- Kolesnikov, Aleks
- Lee, Leslie
- Lesnick, John
- Lewis, Cristina
- Murray, Jeremy
- McLean, Neville J.
- Nonomiya, Jim
- Olivero, Alan G.
- Ord, Rachel
- Pang, Jodie
- Price, Stephen
- Prior, Wei Wei
- Rouge, Lionel
- Salphati, Laurent
- Sampath, Deepak
- Wallin, Jeff
- Wang, Lan
- Wei, BinQing
- Weismann, Christian
- Wu, Ping
- Titel
- Discovery of thiazolobenzoxepin PI3-kinase inhibitors that spare the PI3-kinase β isoform
- Ist Teil von
- Bioorganic & medicinal chemistry letters, 2013-05, Vol.23 (9), p.2606-2613
- Ort / Verlag
- England: Elsevier Ltd
- Erscheinungsjahr
- 2013
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- A series of suitable five-membered heterocyclic alternatives to thiophenes within a thienobenzoxepin class of PI3-kinase (PI3K) inhibitors was discovered. Specific thiazolobenzoxepin 8-substitution was identified that increased selectivity over PI3Kβ. PI3Kβ-sparing compound 27 (PI3Kβ Ki,app/PI3Kα Ki,app=57) demonstrated dose-dependent knockdown of pAKT, pPRAS40 and pS6RP in vivo as well as differential effects in an in vitro proliferation cell line screen compared to pan PI3K inhibitor GDC-0941. A new structure-based hypothesis for reducing inhibition of the PI3K β isoform while maintaining activity against α, δ and γ isoforms is presented.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0960-894XeISSN: 1464-3405DOI: 10.1016/j.bmcl.2013.02.102Titel-ID: cdi_proquest_miscellaneous_1327727636
- Format
- –
- Schlagworte
- Benzoxepins - chemical synthesis, Benzoxepins - chemistry, Benzoxepins - pharmacology, Binding Sites, cell proliferation, Cell Proliferation - drug effects, chemistry, Drug Evaluation, Preclinical, Enzyme Inhibitors - chemical synthesis, Enzyme Inhibitors - chemistry, Enzyme Inhibitors - pharmacology, Humans, Isoform selectivity, MCF-7 Cells, Molecular Docking Simulation, phosphatidylinositol 3-kinase, Phosphatidylinositol 3-Kinase - antagonists & inhibitors, Phosphatidylinositol 3-Kinase - metabolism, PI3-kinase, Protein Isoforms - antagonists & inhibitors, Protein Isoforms - metabolism, Protein Structure, Tertiary, Proto-Oncogene Proteins c-akt - metabolism, Structure-Activity Relationship, Structure-based ligand design, Thiazoles - chemistry, thiophenes