Discovery of an Orally Bioavailable Small Molecule Inhibitor of Prosurvival B-Cell Lymphoma 2 Proteins

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• 作者：Cheol-Min Park ; Milan Bruncko ; Jessica Adickes ; Joy Bauch ; Hong Ding ; Aaron Kunzer ; Kennan C. Marsh ; Paul Nimmer ; Alexander R. Shoemaker ; Xiaohong Song ; Stephen K. Tahir ; Christin Tse ; Xilu Wang ; Mich
• 刊名：Journal of Medicinal Chemistry
• 出版年：2008
• 出版时间：November 13, 2008
• 年：2008
• 卷：51
• 期：21
• 页码：6902-6915
• 全文大小：271K
• 年卷期：v.51,no.21(November 13, 2008)
• ISSN：1520-4804

文摘

Overexpression of prosurvival proteins such as Bcl-2 and Bcl-X_L has been correlated with tumorigenesis and resistance to chemotherapy, and thus, the development of antagonists of these proteins may provide a novel means for the treatment of cancer. We recently described the discovery of 1 (ABT-737), which binds Bcl-2, Bcl-X_L, and Bcl-w with high affinity, shows robust antitumor activity in murine tumor xenograft models, but is not orally bioavailable. Herein, we report that targeted modifications at three key positions of 1 resulted in a 20-fold improvement in the pharmacokinetic/pharmacodynamic relationship (PK/PD) between oral exposure (AUC) and in vitro efficacy in human tumor cell lines (EC₅₀). The resulting compound, 2 (ABT-263), is orally efficacious in an established xenograft model of human small cell lung cancer, inducing complete tumor regressions in all animals. Compound 2 is currently in multiple phase 1 clinical trials in patients with small cell lung cancer and hematological malignancies.