2. Academic Validation
  3. Studies leading to potent, dual inhibitors of Bcl-2 and Bcl-xL

Studies leading to potent, dual inhibitors of Bcl-2 and Bcl-xL

  • J Med Chem. 2007 Feb 22;50(4):641-62. doi: 10.1021/jm061152t.
Milan Bruncko 1,  Thorsten K Oost,  Barbara A Belli,  Hong Ding,  Mary K Joseph,  Aaron Kunzer,  Darlene Martineau,  William J McClellan,  Michael Mitten,  Shi-Chung Ng,  Paul M Nimmer,  Tilman Oltersdorf,  Cheol-Min Park,  Andrew M Petros,  Alexander R Shoemaker,  Xiaohong Song,  Xilu Wang,  Michael D Wendt,  Haichao Zhang,  Stephen W Fesik,  Saul H Rosenberg,  Steven W Elmore
Affiliations

Affiliation

  • 1 Cancer Research, Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois 60064, USA.
PMID: 17256834 DOI: 10.1021/jm061152t
Abstract

Overexpression of the antiapototic proteins Bcl-2 and Bcl-xL provides a common mechanism through which Cancer cells gain a survival advantage and become resistant to conventional chemotherapy. Inhibition of these prosurvival proteins is an attractive strategy for Cancer therapy. We recently described the discovery of a selective Bcl-xL Antagonist that potentiates the antitumor activity of chemotherapy and radiation. Here we describe the use of structure-guided design to exploit a deep hydrophobic binding pocket on the surface of these proteins to develop the first dual, subnanomolar inhibitors of Bcl-xL and Bcl-2. This study culminated in the identification of 2, which exhibited EC50 values of 8 nM and 30 nM in Bcl-2 and Bcl-xL dependent cells, respectively. Compound 2 demonstrated single agent efficacy against human follicular lymphoma cell lines that overexpress Bcl-2, and efficacy in a murine xenograft model of lymphoma when given both as a single agent and in combination with etoposide.

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