1. A small-molecule inhibitor of Bcl-XL potentiates the activity of cytotoxic drugs in vitro and in vivo
- Author
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Paul Nimmer, David Frost, Wang Shen, Mcclellan William J, Jacqueline M. O'Connor, Robert B. Warner, Stephen K. Tahir, Joy Bauch, Alex R. Shoemaker, Shi-Chung Ng, Anatol Oleksijew, Steven W. Elmore, Tony Borre, Tilman Oltersdorf, Haichao Zhang, Mary K. Joseph, Milan Bruncko, Jason Stavropoulos, Kennan C. Marsh, Saul H. Rosenberg, Weiguo Qing, Hugh N. Nellans, Barbara A. Belli, Stephen W. Fesik, Ken Jarvis, Thomas Deckwirth, and Baole Wang
- Subjects
Male ,Cancer Research ,Lung Neoplasms ,Paclitaxel ,Transplantation, Heterologous ,bcl-X Protein ,Bcl-xL ,Antineoplastic Agents ,Mice, SCID ,Biology ,Pharmacology ,Piperazines ,Nitrophenols ,chemistry.chemical_compound ,Mice ,In vivo ,Cell Line, Tumor ,medicine ,Cytotoxic T cell ,Animals ,Humans ,Doxorubicin ,Etoposide ,Cisplatin ,Sulfonamides ,Aniline Compounds ,Biphenyl Compounds ,Biological activity ,Drug Synergism ,Kinetics ,Oncology ,chemistry ,biology.protein ,medicine.drug - Abstract
Inhibition of the prosurvival members of the Bcl-2 family of proteins represents an attractive strategy for the treatment of cancer. We have previously reported the activity of ABT-737, a potent inhibitor of Bcl-2, Bcl-XL, and Bcl-w, which exhibits monotherapy efficacy in xenograft models of small-cell lung cancer and lymphoma and potentiates the activity of numerous cytotoxic agents. Here we describe the biological activity of A-385358, a small molecule with relative selectivity for binding to Bcl-XL versus Bcl-2 (Ki's of 0.80 and 67 nmol/L for Bcl-XL and Bcl-2, respectively). This compound efficiently enters cells and co-localizes with the mitochondrial membrane. Although A-385358 shows relatively modest single-agent cytotoxic activity against most tumor cell lines, it has an EC50 of
- Published
- 2006