title: Lipophilic Isosteres of a π-π Stacking Interaction: New Inhibitors of the Bcl-2-Bak Protein-Protein Interaction.
abstract: The discovery of new Bcl-2 protein-protein interaction antagonists is described. We replaced the northern fragment of ABT737 (π-π stacking interactions) with structurally simplified hydrophobic cage structures with much reduced conformational flexibility and rotational freedom. The binding mode of the compounds was elucidated by X-ray crystallography, and the compounds showed excellent oral bioavailability and clearance in rat PK studies.
authors.affiliation: Novartis Institutes for BioMedical Research Inc., Global Discovery Chemistry, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Naeem
authors.initials: N
authors.lastname: Yusuff
authors.affiliation: Novartis Institutes for BioMedical Research Inc., Global Discovery Chemistry, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Michaël
authors.initials: M
authors.lastname: Doré
authors.affiliation: Novartis Institutes for BioMedical Research Inc., Global Discovery Chemistry, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Carol
authors.initials: C
authors.lastname: Joud
authors.affiliation: Novartis Institutes for BioMedical Research Inc., Global Discovery Chemistry, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Michael
authors.initials: M
authors.lastname: Visser
authors.affiliation: Novartis Institutes for BioMedical Research Inc., Global Discovery Chemistry, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Clayton
authors.initials: C
authors.lastname: Springer
authors.affiliation: Novartis Institutes for BioMedical Research Inc., Global Discovery Chemistry, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Xie
authors.affiliation: Novartis Institutes for BioMedical Research Inc., Global Discovery Chemistry, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Kara
authors.initials: K
authors.lastname: Herlihy
authors.affiliation: Novartis Institutes for BioMedical Research Inc., Global Discovery Chemistry, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Dale
authors.initials: D
authors.lastname: Porter
authors.affiliation: Novartis Institutes for BioMedical Research Inc., Global Discovery Chemistry, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: B Barry
authors.initials: BB
authors.lastname: Touré
keywords: Bcl-2 inhibitors; bioisoteres; cancer therapeutics; protein−protein interaction; π−π stacking interactions; π−π stacking isosteres