title: Discovery of dibenzo[c,f][2,7]naphthyridines as potent and selective 3-phosphoinositide-dependent kinase-1 inhibitors.
abstract: 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.
authors.affiliation: Chemical and Screening Sciences and Oncology, Wyeth Research, 401 N. Middletown Road, Pearl River, NY 10965, USA. gopalsa@wyeth.com
authors.forename: Ariamala
authors.initials: A
authors.lastname: Gopalsamy
authors.forename: Mengxiao
authors.initials: M
authors.lastname: Shi
authors.forename: Diane H
authors.initials: DH
authors.lastname: Boschelli
authors.forename: Robert
authors.initials: R
authors.lastname: Williamson
authors.forename: Andrea
authors.initials: A
authors.lastname: Olland
authors.forename: Yongbo
authors.initials: Y
authors.lastname: Hu
authors.forename: Girija
authors.initials: G
authors.lastname: Krishnamurthy
authors.forename: Xin
authors.initials: X
authors.lastname: Han
authors.forename: Kim
authors.initials: K
authors.lastname: Arndt
authors.forename: Bing
authors.initials: B
authors.lastname: Guo
mesh_terms: 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
chemical_list: D009287:Naphthyridines; D064413:3-Phosphoinositide-Dependent Protein Kinases; D017346:Protein Serine-Threonine Kinases