Knowledge-based design of 7-azaindoles as selective B-Raf inhibitors

Jun Tang; Toshihiro Hamajima; Masato Nakano; Hideyuki Sato; Scott H Dickerson; Karen E Lackey

doi:10.1016/j.bmcl.2008.07.019

Knowledge-based design of 7-azaindoles as selective B-Raf inhibitors

Bioorg Med Chem Lett. 2008 Aug 15;18(16):4610-4. doi: 10.1016/j.bmcl.2008.07.019. Epub 2008 Jul 10.

Authors

Jun Tang¹, Toshihiro Hamajima, Masato Nakano, Hideyuki Sato, Scott H Dickerson, Karen E Lackey

Affiliation

¹ GlaxoSmithKline, Research Triangle Park, NC 27709, USA. [email protected]

PMID: 18662874
DOI: 10.1016/j.bmcl.2008.07.019

Abstract

The synthesis of a 7-azaindole series of novel, potent B-Raf kinase inhibitors using knowledge-based design was carried out. Compound 6h exhibits not only excellent potency in both the enzyme assay (IC(50)=2.5 nM) and the cellular assay (IC(50)=63 nM), but also has an outstanding selectivity profile against other kinases.

MeSH terms

Chemistry, Pharmaceutical / methods*
Drug Design
Humans
Indoles / pharmacology*
Inhibitory Concentration 50
Models, Biological
Models, Chemical
Molecular Structure
Phosphotransferases / metabolism
Protein Kinase Inhibitors / antagonists & inhibitors
Protein Kinase Inhibitors / pharmacology
Proto-Oncogene Proteins B-raf / antagonists & inhibitors*
Proto-Oncogene Proteins B-raf / metabolism*
Structure-Activity Relationship
Substrate Specificity

Substances

Indoles
Protein Kinase Inhibitors
Phosphotransferases
Proto-Oncogene Proteins B-raf