title: Discovery of a potent inhibitor of the antiapoptotic protein Bcl-xL from NMR and parallel synthesis.
abstract: The antiapoptotic proteins Bcl-x(L) and Bcl-2 play key roles in the maintenance of normal cellular homeostasis. However, their overexpression can lead to oncogenic transformation and is responsible for drug resistance in certain types of cancer. This makes Bcl-x(L) and Bcl-2 attractive targets for the development of potential anticancer agents. Here we describe the structure-based discovery of a potent Bcl-x(L) inhibitor directed at a hydrophobic groove on the surface of the protein. This groove represents the binding site for BH3 peptides from proapoptotic Bcl-2 family members such as Bak and Bad. Application of NMR-based screening yielded an initial biaryl acid with an affinity (K(d)) of approximately 300 microM for the protein. Following the classical "SAR by NMR" approach, a second-site ligand was identified that bound proximal to the first-site ligand in the hydrophobic groove. From NMR-based structural studies and parallel synthesis, a potent ligand was obtained, which binds to Bcl-x(L) with an inhibition constant (K(i)) of 36 +/- 2 nM.
authors.affiliation: Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois 60064, USA.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Petros
authors.forename: Jurgen
authors.initials: J
authors.lastname: Dinges
authors.forename: David J
authors.initials: DJ
authors.lastname: Augeri
authors.forename: Steven A
authors.initials: SA
authors.lastname: Baumeister
authors.forename: David A
authors.initials: DA
authors.lastname: Betebenner
authors.forename: Mark G
authors.initials: MG
authors.lastname: Bures
authors.forename: Steven W
authors.initials: SW
authors.lastname: Elmore
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Hajduk
authors.forename: Mary K
authors.initials: MK
authors.lastname: Joseph
authors.forename: Shelley K
authors.initials: SK
authors.lastname: Landis
authors.forename: David G
authors.initials: DG
authors.lastname: Nettesheim
authors.forename: Saul H
authors.initials: SH
authors.lastname: Rosenberg
authors.forename: Wang
authors.initials: W
authors.lastname: Shen
authors.forename: Sheela
authors.initials: S
authors.lastname: Thomas
authors.forename: Xilu
authors.initials: X
authors.lastname: Wang
authors.forename: Irini
authors.initials: I
authors.lastname: Zanze
authors.forename: Haichao
authors.initials: H
authors.lastname: Zhang
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Fesik
mesh_terms: D000814:Aniline Compounds / Q000138:chemical synthesis* / Q000737:chemistry; D001665:Binding Sites; D057927:Hydrophobic and Hydrophilic Interactions; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D011485:Protein Binding; D012995:Solubility; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry; D051020:bcl-X Protein / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000096926:Benzenesulfonamides
chemical_list: D000814:Aniline Compounds; D008024:Ligands; D013449:Sulfonamides; D051020:bcl-X Protein; C508798:N-(4'-fluorobiphenyl-4-ylcarbonyl)-3-nitro-4-(2-phenylsulfanylethylamino)benzenesulfonamide; D000096926:Benzenesulfonamides