title: The role of the acidity of N-heteroaryl sulfonamides as inhibitors of bcl-2 family protein-protein interactions.
abstract: Overexpression of the antiapoptotic members of the Bcl-2 family of proteins is commonly associated with cancer cell survival and resistance to chemotherapeutics. Here, we describe the structure-based optimization of a series of N-heteroaryl sulfonamides that demonstrate potent mechanism-based cell death. The role of the acidic nature of the sulfonamide moiety as it relates to potency, solubility, and clearance is examined. This has led to the discovery of novel heterocyclic replacements for the acylsulfonamide core of ABT-737 and ABT-263.
authors.affiliation: Novartis Institutes for BioMedical Research Inc. , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: B Barry
authors.initials: BB
authors.lastname: Touré
authors.affiliation: Novartis Institutes for BioMedical Research Inc. , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Karen
authors.initials: K
authors.lastname: Miller-Moslin
authors.affiliation: Novartis Institutes for BioMedical Research Inc. , 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. , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Perez
authors.affiliation: Novartis Institutes for BioMedical Research Inc. , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Michael
authors.initials: M
authors.lastname: Doré
authors.affiliation: Novartis Institutes for BioMedical Research Inc. , 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. , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Walter
authors.initials: W
authors.lastname: Michael
authors.affiliation: Novartis Institutes for BioMedical Research Inc. , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Lucian
authors.initials: L
authors.lastname: DiPietro
authors.affiliation: Novartis Institutes for BioMedical Research Inc. , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Simon
authors.initials: S
authors.lastname: van der Plas
authors.affiliation: Novartis Institutes for BioMedical Research Inc. , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Michael
authors.initials: M
authors.lastname: McEwan
authors.affiliation: Novartis Institutes for BioMedical Research Inc. , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Francois
authors.initials: F
authors.lastname: Lenoir
authors.affiliation: Novartis Institutes for BioMedical Research Inc. , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Madelene
authors.initials: M
authors.lastname: Hoe
authors.affiliation: Novartis Institutes for BioMedical Research Inc. , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Karki
authors.affiliation: Novartis Institutes for BioMedical Research Inc. , 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. , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: John
authors.initials: J
authors.lastname: Sullivan
authors.affiliation: Novartis Institutes for BioMedical Research Inc. , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Kymberly
authors.initials: K
authors.lastname: Levine
authors.affiliation: Novartis Institutes for BioMedical Research Inc. , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Catherine
authors.initials: C
authors.lastname: Fiorilla
authors.affiliation: Novartis Institutes for BioMedical Research Inc. , 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. , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Raviraj
authors.initials: R
authors.lastname: Kulathila
authors.affiliation: Novartis Institutes for BioMedical Research Inc. , 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. , 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. , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Michael
authors.initials: M
authors.lastname: Visser
keywords: B cell lymphoma; Bcl-2 family; apoptosis; cancer; protein−protein interaction