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Park, Cheol-Min
Synthetic & Medicinal Chemistry Lab
Research Interests
  • Organic synthesis, medicinal chemistry, chemical biology

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

Cited 142 times inthomson ciCited 135 times inthomson ci
Title
Studies leading to potent, dual inhibitors of bcl-2 and Bcl-xL
Author
Bruncko, MilanOost, Thorsten K.Belli, Barbara A.Ding, HongJoseph, Mary K.Kunzer, AaronMartineau, DarleneMcClellan, William J.Mitten, Michaelng, Shi-Chu NgNimmer, Paul M.Oltersdorf, TilmanPark, Cheol-MinPetros, Andrew M.Shoemaker, Alexander R.Song, XiaohongWang, XiluWendt, Michael D.Zhang, HaichaoFesik, Stephen W.Rosenberg, Saul H.Elmore, Steven W.
Keywords
IN-VIVO; CASPASE ACTIVATION; FAMILY PROTEINS; CELL-LINES; APOPTOSIS; DEATH; CANCER; LIFE; ANTAGONISTS; MECHANISMS
Issue Date
2007-02
Publisher
AMER CHEMICAL SOC
Citation
JOURNAL OF MEDICINAL CHEMISTRY, v.50, no.4, pp.641 - 662
Abstract
verexpression 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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DOI
10.1021/jm061152t
ISSN
0022-2623
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PHY_Journal Papers
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