Mini-Reviews in Organic Chemistry, 2008, 5, 171-178 171 1570-193X/08 $55.00+.00 © 2008 Bentham Science Publishers Ltd. Antagonists Against Anti-Apoptotic Bcl-2 Family Proteins for Cancer Treatment Jignesh M. Doshi and Chengguo Xing* Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, 8-101 WDH, 308 Harvard St S. E., Minneapolis MN 55455, USA Abstract: Apoptosis is a programmed cell death process, critical for normal cellular development and tissue homeostasis. B-cell lymphocyte/leukemia 2 (Bcl-2) family proteins are important regulators of apoptosis. Numerous studies have dem- onstrated that over-expressing anti-apoptotic Bcl-2 proteins is one mechanism for cancer cells to acquire resistance against cancer chemotherapies, suggesting antagonizing these proteins would be a potential approach to overcoming such drug re- sistance. This review briefly discusses the principle and the recent advances in the development of such antagonists, with some highlights about several promising antagonists. Keywords: Bcl-2 antagonists, drug resistance, apoptosis, cancer. INTRODUCTION Apoptosis is a highly regulated and energy-dependent process of cellular suicide that can be triggered by a multi- tude of internal and external stimuli [1]. Apoptosis plays an important role in many developmental processes as well as maintenance of tissue homeostasis. Indeed, impaired apopto- sis is a hallmark of various cancers [2]. As many cancer therapies eliminate tumor cells through induction of apopto- sis directly or indirectly, impairment in apoptosis also leads to drug resistance to cancer therapies [3]. REGULATION OF LIFE AND DEATH BY THE BCL-2 FAMILY PROTEINS One mechanism for cancers to acquire resistance to apop- tosis is through the over-expression of anti-apoptotic Bcl-2 family proteins, a subfamily of Bcl-2 family proteins. Bcl-2 family proteins comprise of over 20 members, which are the crucial regulators of apoptosis [4]. The Bcl-2 family proteins can be functionally classified into two broad subfamilies. The first subfamily comprise of family members that protect a cell from apoptosis, named as anti-apoptotic Bcl-2 proteins (Bcl-2, Bcl-X L , Bcl-w, Mcl-1, A-1, and Bcl-B) [5, 6]. The *Address correspondence to this author at the Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, 8-101 WDH, 308 Harvard St S. E., Minneapolis MN 55455, USA; Tel: 612-626-5675; Fax: 612-624-0139; E-mail: xingx009@umn.edu other subfamily consists of family members that promote apoptosis, named pro-apoptotic Bcl-2 proteins. These two subfamilies antagonize each other and the balance between them determines the cell’s fate to undergo apoptosis or to survive. Most of the anti-apoptotic members contain four conserved motifs named as Bcl-2 homology (BH) domains (BH1 – BH4) except Mcl-1 contains only three conserved domains (BH1 – BH3) and lacks the BH4 domain [7] (Fig. 1). The pro-apoptotic Bcl-2 proteins can be further classified into two subsets. Some members (Bax, Bak, and Bok) have three BH domains (BH1, BH2, and BH3) while other mem- bers only have BH3 domain, named as BH3-domain only pro-apoptotic Bcl-2 proteins (Bik, Bid, Bad, Bim, Bmf, Hrk, Noxa, and Puma) [8]. Structural studies have revealed that the BH1, BH2, and BH3 domains in the anti-apoptotic pro- teins are folded to form an elongated hydrophobic cleft. This cleft serves as the binding site to interact with the pro- apoptotic members through their BH3 domain, forming het- erodimer [9, 10]. Heterodimerization of a pro-apoptotic Bcl- 2 family member and an anti-apoptotic Bcl-2 family member is one proposed mechanism for these two subfamilies to an- tagonize each other. The anti-apoptotic Bcl-2 family proteins engage pro-apoptotic Bcl-2 proteins and keep them in check, thereby preventing apoptosis. The pro-apoptotic Bcl-2 fam- ily proteins, when in excess or activated (not bound by anti- apoptotic ones), can permeabilize the mitochondrial mem- brane, resulting in the leakage of cytochrome c and other molecules involved in caspase activation, which leads to apoptosis [11, 12]. Fig. (1). Schematic representation of structural domains of the Bcl-2 family proteins.