HDM2 regulates p53 by binding to its transactivation domain and promoting its ubiquitin‐dependent degradation. Crystallographic analysis of the HDM2/p53 complex revealed that three hydrophobic residues (F19, W23, L26) along one face of the p53 helical peptide are essential for binding (see picture). Terphenyl‐based antagonists mimic the α‐helical region of p53 and disrupt HDM2/p53 complexation.

A series of Bcl-x(L)/Bak antagonists, based on a terephthalamide scaffold, was designed to mimic the alpha-helical region of the Bak peptide. These molecules showed favorable in vitro activities in disrupting the Bcl-x(L)/Bak BH3 domain complex (terephthalamides 9 and 26, K(i) = 0.78 +/- 0.07 and 1.85 +/- 0.32 microM, respectively). Extensive structure-affinity studies demonstrated a correlation between the ability of terephthalamide derivatives to disrupt Bcl-x(L)/Bak complex formation and the size of variable side chains on these molecules. Treatment of human HEK293 cells with the terephthalamide derivative 26 resulted in disruption of the Bcl-x(L)/Bax interaction in whole cells with an IC(50) of 35.0 microM. Computational docking simulations and NMR experiments suggested that the binding cleft for the BH3 domain of the Bak peptide on the surface of Bcl-x(L) is the target area for these synthetic inhibitors.

A critical hallmark of cancer cell survival is evasion of apoptosis. This is commonly due to overexpression of anti-apoptotic proteins such as Bcl-2, Bcl-X L , and Mcl-1, which bind to the BH3 ␣-helical domain of pro-apoptotic proteins such as Bax, Bak, Bad, and Bim, and inhibit their function. We designed a BH3 ␣-helical mimetic BH3-M6 that binds to Bcl-X Apoptosis, a form of programmed cell death, is a highly conserved process in all multicellular organisms and is essential for embryonic development and adult tissue homeostasis. Deregulation of apoptosis contributes to several diseases including cancer (1). Apoptosis is primarily controlled by two major pathways, namely the death receptor (extrinsic) and the mitochondrial (intrinsic) pathways (2). The former is mediated by members of the tumor necrosis factor (TNF) 6 receptor superfamily, while the latter largely depends on multiple Bcl-2 family proteins, which affect the integrity of the mitochondrial outer membrane (MOM) (3). Both pathways converge on common cysteine proteases of the caspase family, which are responsible for the execution of apoptosis (4).The Bcl-2 family consists of anti-apoptotic and pro-apoptotic proteins. Anti-apoptotic proteins, such as Bcl-2, Bcl-X L , Bcl-w, Mcl-1, and Bfl-1 (Bcl-2A1) contain four Bcl-2 homology (BH) domains, while the pro-apoptotic members are divided into proteins with three BH domains BH1-BH3 (Bax, Bak, and Bok), and proteins with only a BH3 domain (e.g. Bim, Bad, Bik, Bmf, Bid, Noxa, and Puma) (5). Multi-domain proapoptotic proteins Bax and Bak are absolutely required for apoptosis (2). In response to cellular stress, they induce the release from mitochondria of apoptogenic factors such as cytochrome c, which then cooperate with APAF-1 to induce caspase-9 activation, followed by caspase-mediated apoptosis (6). BH3-only proteins act upstream of Bax and Bak and are important for the initiation of apoptosis. Importantly, the BH3 domain is essential for the killing function of pro-apoptotic proteins (7).An important feature of the Bcl-2 proteins is that they can homo-and heterodimerize, giving rise to three competing, but not necessarily exclusive models that could explain how the balance between pro-and anti-apoptotic proteins regulates apoptosis (7). For instance, upon receiving an apoptotic signal, BH3-only proteins directly or indirectly induce Bax and Bak activation and homo-oligomerization in the MOM, which is thought to be responsible for MOM permeabilization, resulting in the release of cytochrome c and the initiation of intrinsic apoptosis. However, activated Bax and Bak still can be kept in check by binding to anti-apoptotic Bcl-2 proteins (8 -10). X-ray diffraction and nuclear magnetic resonance (NMR) studies have shown that the amphipathic ␣-helices of pro-apoptotic proteins such as Bak or Bad BH3 domains fit into a hydrophobic pocket formed by the BH1, BH2, * This work was funded, in whole or in part, by National Institutes of Health P01 Grants CA118210 and GM69850.

Not‐so‐short and curlies: A new benzoylurea‐based foldamer scaffold favors a linear conformation governed by intramolecular hydrogen bonding (see picture, left). The functional groups R are in a staggered arrangement analogous to an α helix. Iterative synthesis and diversification of the functional groups leads to structures with lengths similar to those of naturally occurring α helices (right).

HDM2 reguliert p53, indem es an seine Transaktivierungsdomäne bindet und seinen Ubiquitin‐abhängigen Abbau fördert. Aus der Kristallstrukturanalyse des HDM2/p53‐Komplexes folgt, dass drei hydrophobe Reste (F19, W23, L26) entlang einer Seite des helicalen p53‐Peptids für das Binden essenziell sind (siehe Bild). Terphenyl‐basierte Antagonisten ahmen die α‐helicale Region von p53 nach und unterbrechen die HDM2/p53‐Komplexierung.