Discovery and optimization of thieno[2,3-d]pyrimidines as B-Raf inhibitors

The serine/threonine specific protein kinase B-Raf is part of the MAPK pathway and is an interesting oncology target. We have identified thieno[2,3-d]pyrimidines as a core scaffold of small molecule B-Raf inhibitors. The SAR of analogs in this series will be described.

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2012-01, Vol.22 (1), p.747-752
Main Authors: Packard, Garrick K., Papa, Patrick, Riggs, Jennifer R., Erdman, Paul, Tehrani, Lida, Robinson, Dale, Harris, Roy, Shevlin, Graziella, Perrin-Ninkovic, Sophie, Hilgraf, Robert, McCarrick, Margaret A., Tran, Tam, Fleming, Yuedi, Bai, April, Richardson, Samantha, Katz, Jason, Tang, Yang, Leisten, Jim, Moghaddam, Mehran, Cathers, Brian, Zhu, Dan, Sakata, Steven
Format: Article
Language:English
Subjects:
B-Raf inhibitor
Biological and medical sciences
Chemistry, Pharmaceutical - methods
Crystallography, X-Ray - methods
Cyclic Nucleotide Phosphodiesterases, Type 4 - chemistry
Drug Design
Humans
Inhibitory Concentration 50
MAP Kinase Signaling System
Medical sciences
Models, Chemical
PDE4 inhibitor
Pharmacology. Drug treatments
Protein Isoforms
Protein Kinase Inhibitors - chemical synthesis
Protein Kinase Inhibitors - pharmacology
Proto-Oncogene Proteins B-raf - antagonists & inhibitors
Proto-Oncogene Proteins B-raf - metabolism
Pyrimidines - pharmacology
Structure-Activity Relationship
Thieno[2,3-d]pyrimidine
Urea - chemistry
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Description
Summary:The serine/threonine specific protein kinase B-Raf is part of the MAPK pathway and is an interesting oncology target. We have identified thieno[2,3-d]pyrimidines as a core scaffold of small molecule B-Raf inhibitors. The SAR of analogs in this series will be described.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2011.03.006