Design, synthesis and evaluation of a new class of potent and cell-permeable small molecule inhibitors of Bcl-2 and Mcl-1

MEDI 97

Guozhi Tang, tanggle@med.umich.edu1, Ke Ding2, Jie Guo1, Zaneta Nikolovska-Coleska2, Chao-Yie Yang2, Renxiao Wang1, Jianting Long1, Su Qiu2, Sanjeev Kumar2, Wei Gao2, Jeanne Stuckey3, Krzysztof Krajewski4, Sheng Jiang5, Peter P. Roller5, and Shaomeng Wang, shaomeng@umich.edu2. (1) Departments of Internal Medicine and Medicinal Chemistry, University of Michigan, 1500 E. Medical Center Dr, Ann Arbor, MI 48109-0934, (2) Comprehensive Cancer Center and Departments of Internal Medicine, Pharmacology and Medicinal Chemistry, The University of Michigan, 1500 E. Medical Center Dr, CCGC/3316, Ann Arbor, MI 48109-0934, (3) Life Sciences Institute, The University of Michigan, Ann Arbor, MI 48109, (4) Laboratory of Medicinal Chemistry, National Cancer Institute, National Institutes of Health, 376 Boyles Street, Frederick, MD 21702-1201, (5) Laboratory of Medicinal Chemistry, National Cancer Institute, NIH, 376 Boyles Street, Frederick, MD 21702-1201
Anti-apoptotic Bcl-2 proteins, including Bcl-2 and Mcl-1 are attractive molecular targets for the design of a new class of anticancer therapy aiming at promoting apoptosis in cancer cells. These anti-apoptotic proteins inhibit apoptosis in cells through hetero-dimerization with pro-apoptotic Bcl-2 members such as Bid, Bim and Bad proteins. In this presentation, we wish to describe the design, synthesis, biochemical and biological evaluation of a new class of small-molecule inhibitors targeting multiple anti-apoptotic Bcl-2 members. These small-molecule inhibitors bind to Bcl-2 and Mcl-1 proteins with low nanomolar affinities and are highly effective in induction of apoptosis in cancer cells on their own. They represent promising lead compounds for further extensive evaluations in vitro and in vivo.
 

General Poster Session
7:00 PM-9:00 PM, Sunday, 10 September 2006 Moscone Center -- Hall D, Poster

Division of Medicinal Chemistry

The 232nd ACS National Meeting, San Francisco, CA, September 10-14, 2006