Studies Leading to Potent, Dual Inhibitors of Bcl-2 and Bcl-xL

• Published in: Journal of medicinal chemistry Vol. 50; no. 4; pp. 641 - 662
• Main Authors: Bruncko, Milan, Oost, Thorsten K, Belli, Barbara A, Ding, Hong, Joseph, Mary K, Kunzer, Aaron, Martineau, Darlene, McClellan, William J, Mitten, Michael, Ng, Shi-Chung, Nimmer, Paul M, Oltersdorf, Tilman, Park, Cheol-Min, Petros, Andrew M, Shoemaker, Alexander R, Song, Xiaohong, Wang, Xilu, Wendt, Michael D, Zhang, Haichao, Fesik, Stephen W, Rosenberg, Saul H, Elmore, Steven W
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 22.02.2007; Amer Chemical Soc
• Subjects: Animals; Antineoplastic agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; bcl-X Protein - antagonists & inhibitors; bcl-X Protein - chemistry; Biological and medical sciences; Biphenyl Compounds - chemical synthesis; Biphenyl Compounds - chemistry; Biphenyl Compounds - pharmacology; Cell Line, Tumor; Chemistry, Medicinal; Drug Screening Assays, Antitumor; General aspects; Humans; Life Sciences & Biomedicine; Lymphoma; Medical sciences; Mice; Mice, SCID; Models, Molecular; Nitrophenols - chemical synthesis; Nitrophenols - chemistry; Nitrophenols - pharmacology; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Piperazines - chemical synthesis; Piperazines - chemistry; Piperazines - pharmacology; Proto-Oncogene Proteins c-bcl-2 - antagonists & inhibitors; Proto-Oncogene Proteins c-bcl-2 - chemistry; Science & Technology; Structure-Activity Relationship; Sulfonamides - chemical synthesis; Sulfonamides - chemistry; Sulfonamides - pharmacology; Transplantation, Heterologous; IN-VITRO; ACTIVATION; ETOPOSIDE; MECHANISMS; REGULATORS; FAMILY PROTEINS; ANTAGONISTS; BINDING; LIFE; Antineoplastic agent; Nitro compound; Hematopoietic cell; Modeling; Imide; Structure activity relation; Molecular model; Chemical synthesis; Fluorescence polarization; Drug combination; Sulfonamide; Rodentia; Etoposide; Aminosulfide; Organic chlorine compounds; In vitro; Diamine; In vivo; Vertebrata; Mammalia; Mouse; Biphenyl derivatives; Animal; Carboxamide; Inhibitor; Piperazine derivatives; Apoptosis
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm061152t

Overexpression of the antiapototic proteins Bcl-2 and Bcl-xL provides a common mechanism through which cancer cells gain a survival advantage and become resistant to conventional chemotherapy. Inhibition of these prosurvival proteins is an attractive strategy for cancer therapy. We recently described the discovery of a selective Bcl-xL antagonist that potentiates the antitumor activity of chemotherapy and radiation. Here we describe the use of structure-guided design to exploit a deep hydrophobic binding pocket on the surface of these proteins to develop the first dual, subnanomolar inhibitors of Bcl-xL and Bcl-2. This study culminated in the identification of 2, which exhibited EC50 values of 8 nM and 30 nM in Bcl-2 and Bcl-xL dependent cells, respectively. Compound 2 demonstrated single agent efficacy against human follicular lymphoma cell lines that overexpress Bcl-2, and efficacy in a murine xenograft model of lymphoma when given both as a single agent and in combination with etoposide.