| Literature DB >> 18841882 |
Cheol-Min Park1, 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, Michael D Wendt, Xiufen Yang, Haichao Zhang, Stephen W Fesik, Saul H Rosenberg, Steven W Elmore.
Abstract
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 (EC 50). 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.Entities:
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Year: 2008 PMID： 18841882 DOI： 10.1021/jm800669s
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446