Studies leading to potent, dual inhibitors of Bcl-2 and Bcl-xL.

Bruncko M, Oost TK, Belli BA, Ding H, Joseph MK, Kunzer A, Martineau D, McClellan WJ, Mitten M, Ng SC, Nimmer PM, Oltersdorf T, Park CM, Petros AM, Shoemaker AR, Song X, Wang X, Wendt MD, Zhang H, Fesik SW, Rosenberg SH, Elmore SW
J Med Chem. 2007 50 (4): 641-62

PMID: 17256834 · 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.

MeSH Terms (17)

Animals Antineoplastic Agents bcl-X Protein Biphenyl Compounds Cell Line, Tumor Drug Screening Assays, Antitumor Humans Lymphoma Mice Mice, SCID Models, Molecular Nitrophenols Piperazines Proto-Oncogene Proteins c-bcl-2 Structure-Activity Relationship Sulfonamides Transplantation, Heterologous

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