Prev. Article Next Article Table of Contents

Article

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

Supporting Info

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, Michael D. Wendt, Xiufen Yang, Haichao Zhang, Stephen W. Fesik, Saul H. Rosenberg and Steven W. Elmore*

Cancer Research, Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois 60064

J. Med. Chem., 2008, 51 (21), pp 6902–6915

DOI: 10.1021/jm800669s

Publication Date (Web): October 8, 2008

†

These authors contributed equally to this work.

* To whom correspondence should be addressed. Phone: (847) 937-7850. Fax: (847) 938-1004. E-mail: Steve.elmore@abbott.com.

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 (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.

View: Full Text HTML | Hi-Res PDF | PDF w/ Links

Tools

SciFinder Links

History

Published In Issue November 13, 2008
Article ASAPOctober 08, 2008
Received: June 3, 2008

Recommend & Share

Related Content

Discovery and Structure−Activity Relationship of Antagonists of B-Cell Lymphoma 2 Family Proteins with Chemopotentiation Activity in Vitro and in VivoJournal of Medicinal Chemistry
- Discovery and Structure−Activity Relationship of Antagonists of B-Cell Lymphoma 2 Family Proteins with Chemopotentiation Activity in Vitro and in Vivo
  Michael D. Wendt, Wang Shen, Aaron Kunzer, William J. McClellan, Milan Bruncko, Thorsten K. Oost, Hong Ding, Mary K. Joseph, Haichao Zhang, Paul M. Nimmer, Shi-Chung Ng, Alexander R. Shoemaker, Andrew M. Petros, Anatol Oleksijew, Kennan Marsh, Joy Bauch, Tilman Oltersdorf, Barbara A. Belli, Darlene Martineau, Stephen W. Fesik, Saul H. Rosenberg, and Steven W. Elmore
  Journal of Medicinal Chemistry 2006 49 (3), pp 1165–1181
  Abstract: Development of a rationally designed potentiator of cancer chemotherapy, via inhibition of Bcl-X_L function, is described. Lead compounds generated by NMR screening and directed parallel synthesis displayed sub-μM binding but were strongly deactivated in ...
  Abstract | Full Text HTML | Hi-Res PDF
Design, Synthesis, and Computational Studies of Inhibitors of Bcl-X_LJournal of the American Chemical Society
- Design, Synthesis, and Computational Studies of Inhibitors of Bcl-X_L
  Cheol-Min Park, Tetsuro Oie, Andrew M. Petros, Haichao Zhang, Paul M. Nimmer, Rodger F. Henry, and Steven W. Elmore
  Journal of the American Chemical Society 2006 128 (50), pp 16206–16212
  Abstract: One of the primary objectives in the design of protein inhibitors is to shape the three-dimensional structures of small molecules to be complementary to the binding site of a target protein. In the course of our efforts to discover potent inhibitors of ...
  Abstract | Full Text HTML | Hi-Res PDF
Discovery of a Potent Inhibitor of the Antiapoptotic Protein Bcl-x_L from NMR and Parallel SynthesisJournal of Medicinal Chemistry
- Discovery of a Potent Inhibitor of the Antiapoptotic Protein Bcl-x_L from NMR and Parallel Synthesis
  Andrew M. Petros, Jurgen Dinges, David J. Augeri, Steven A. Baumeister, David A. Betebenner, Mark G. Bures, Steven W. Elmore, Philip J. Hajduk, Mary K. Joseph, Shelley K. Landis, David G. Nettesheim, Saul H. Rosenberg, Wang Shen, Sheela Thomas, Xilu Wang, Irini Zanze, Haichao Zhang, and Stephen W. Fesik
  Journal of Medicinal Chemistry 2006 49 (2), pp 656–663
  Abstract: The antiapoptotic proteins Bcl-x_L and Bcl-2 play key roles in the maintenance of normal cellular homeostasis. However, their overexpression can lead to oncogenic transformation and is responsible for drug resistance in certain types of cancer. This makes ...
  Abstract | Full Text HTML | Hi-Res PDF

Article

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