Discovery of an Orally Bioavailable Small Molecule Inhibitor of Prosurvival B-Cell Lymphoma 2 Proteins
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- Discovery of an Orally Bioavailable Small Molecule Inhibitor of Prosurvival B-Cell Lymphoma 2 Proteins
- Park, Cheol-Min; Bruncko, Milan; Adickes, Jessica; Bauch, Joy; Ding, Hong; Kunzer, Aaron; Marsh, Kennan C.; Nimmer, Paul; Shoemaker, Alexander R.; Song, Xiaohong; Tahir, Stephen K.; Tse, Christin; Wang, Xilu; Wendt, Michael D.; Yang, Xiufen; Zhang, Haichao; Fesik, Stephen W.; Rosenberg, Saul H.; Elmore, Steven W.
- Issue Date
- AMER CHEMICAL SOC
- JOURNAL OF MEDICINAL CHEMISTRY, v.51, no.21, pp.6902 - 6915
- Overexpression of prosurvival proteins such as Bcl-2 and Bcl-XL 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-XL, 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.
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