Discovery of an orally bioavailable small molecule inhibitor of prosurvival B-cell lymphoma 2 proteins.

作者: Cheol-Min Park , Milan Bruncko , Jessica Adickes , Joy Bauch , Hong Ding

DOI: 10.1021/JM800669S

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摘要: Overexpression of prosurvival proteins such as Bcl-2 and Bcl-XL has been correlated with tumorigenesis resistance to chemotherapy, thus, the development antagonists these may provide a novel means for treatment cancer. We recently described discovery 1 (ABT-737), which binds Bcl-2, Bcl-XL, Bcl-w 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 resulted 20-fold improvement pharmacokinetic/pharmacodynamic relationship (PK/PD) between oral exposure (AUC) vitro efficacy human cell lines (EC50). The resulting compound, 2 (ABT-263), efficacious an established model small lung cancer, inducing complete regressions all animals. Compound currently multiple phase clinical trials patients cancer hematological malignancies.

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