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

  • J Med Chem. 2008 Nov 13;51(21):6902-15. doi: 10.1021/jm800669s.
Cheol-Min Park  1 ,  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
Affiliations
  • 1. Cancer Research, Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois 60064, USA.
PMID: 18841882 DOI: 10.1021/jm800669s
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.