Discovery of a Potent Inhibitor of the Antiapoptotic Protein Bcl-xL from NMR and Parallel Synthesis

• Published in: Journal of medicinal chemistry Vol. 49; no. 2; pp. 656 - 663
• Main Authors: Petros, Andrew M, Dinges, Jurgen, Augeri, David J, Baumeister, Steven A, Betebenner, David A, Bures, Mark G, Elmore, Steven W, Hajduk, Philip J, Joseph, Mary K, Landis, Shelley K, Nettesheim, David G, Rosenberg, Saul H, Shen, Wang, Thomas, Sheela, Wang, Xilu, Zanze, Irini, Zhang, Haichao, Fesik, Stephen W
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 26-01-2006
• Subjects: Aniline Compounds - chemical synthesis; Aniline Compounds - chemistry; Antineoplastic agents; bcl-X Protein - antagonists & inhibitors; bcl-X Protein - chemistry; Binding Sites; Biological and medical sciences; General aspects; Hydrophobic and Hydrophilic Interactions; Ligands; Magnetic Resonance Spectroscopy; Medical sciences; Models, Molecular; Pharmacology. Drug treatments; Protein Binding; Solubility; Structure-Activity Relationship; Sulfonamides - chemical synthesis; Sulfonamides - chemistry; Imide; Antiapoptotic agent; Sulfonamide; Structure activity relation; Biphenyl derivatives; Combinatorial chemistry; Carboxamide; Inhibitor; NMR spectrometry; Chemical synthesis; In vitro; Protein
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm0507532

The antiapoptotic proteins Bcl-xL 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-xL and Bcl-2 attractive targets for the development of potential anticancer agents. Here we describe the structure-based discovery of a potent Bcl-xL 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 ∼300 μM 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-xL with an inhibition constant (K i) of 36 ± 2 nM.