Discovery of dibenzo[c,f][2,7]naphthyridines as potent and selective 3-phosphoinositide-dependent kinase-1 inhibitors.
With high-throughput screening, substituted dibenzo[c,f][2,7]naphthyridine 1 was identified as a novel potent and selective phosphoinositide-dependent kinase-1 (PDK-1) inhibitor. Various regions of the lead molecule were explored to understand the SAR requirement for this scaffold. The crystal structure of 1 with kinase domain of PDK-1 confirmed the binding in the active site. The key interaction of the molecule with the active site residues, observed SAR, and the biological profile are discussed in detail.
Gopalsamy
Ariamala
A
Chemical and Screening Sciences and Oncology, Wyeth Research, 401 N. Middletown Road, Pearl River, NY 10965, USA. gopalsa@wyeth.com
Shi
Mengxiao
M
Boschelli
Diane H
DH
Williamson
Robert
R
Olland
Andrea
A
Hu
Yongbo
Y
Krishnamurthy
Girija
G
Han
Xin
X
Arndt
Kim
K
Guo
Bing
B
D064413:3-Phosphoinositide-Dependent Protein Kinases; D001665:Binding Sites; D018360:Crystallography, X-Ray; D008958:Models, Molecular; D015394:Molecular Structure; D009287:Naphthyridines / Q000138:chemical synthesis* / Q000737:chemistry; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013329:Structure-Activity Relationship
D009287:Naphthyridines; D064413:3-Phosphoinositide-Dependent Protein Kinases; D017346:Protein Serine-Threonine Kinases