Discovery of a potent inhibitor of the antiapoptotic protein Bcl-xL from NMR and parallel synthesis.
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.
Petros
Andrew M
AM
Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois 60064, USA.
Dinges
Jurgen
J
Augeri
David J
DJ
Baumeister
Steven A
SA
Betebenner
David A
DA
Bures
Mark G
MG
Elmore
Steven W
SW
Hajduk
Philip J
PJ
Joseph
Mary K
MK
Landis
Shelley K
SK
Nettesheim
David G
DG
Rosenberg
Saul H
SH
Shen
Wang
W
Thomas
Sheela
S
Wang
Xilu
X
Zanze
Irini
I
Zhang
Haichao
H
Fesik
Stephen W
SW
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
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