Tests new post that evaluated liver function showed no elevation in transami nases or LDH in any of the animals. Inhibitors,Modulators,Libraries These results suggest that JY 1 106 can be administered safely as there are no sig nificant toxicity effects. The effects of JY 1 106 on tumor growth were further evaluated by administering this agent to nude mice bearing flank human lung cancer xenografts. Tumor bearing mice were randomly divided into two treatment groups, a vehicle control group and JY 1 106 therapy group. The overall effects of these treatments on tumor growth were analyzed using an ANOVA statistical method. Treatment with JY 1 106 significantly inhibited tumor growth in comparison to the vehicle control.

Discussion The ability of anti apoptotic proteins to promote cancer cell survival depends on protein protein interactions between the BH3 domains of pro apoptotic proteins and the BH3 binding hydrophobic grooves of anti apoptotic proteins. This interaction is defined by the binding of the amphipathic helical BH3 domain from multi BH domain proteins, Inhibitors,Modulators,Libraries such as Bax and Bak, as well as BH3 domain only proteins, such as Bim, Bid, NOXA, Bad and PUMA, to a hydrophobic pocket formed by the BH1, BH2, and BH3 domains at the surface of anti apoptotic proteins, such as Bcl 2, Bcl xL and Mcl 1. In this way, the anti apoptotic Bcl 2 proteins neutralize the cell killing function of their pro apoptotic counter parts. This interaction prompted the idea that BH3 do main mimetics may serve as potential novel anti cancer drugs.

In this report, we characterize the novel helix mi metic JY 1 106 that disrupts the interactions between both Bcl xL and Mcl 1 with Bak, which leads to apop tosis through the mitochondrial pathway in human cancer cells. Unlike several Bcl 2 antagonists Inhibitors,Modulators,Libraries such as gossypol, apogossypolone, TW 37, obatoclax, ABT 737, ABT 263, HA1 41, chelerythrine, antimycin and BHI Inhibitors,Modulators,Libraries 1, JY 1 106 was designed using an helix mimicry strat egy involving a trisarylamide scaffold to spatially project functionality in a manner similar to that of two turns of the Bak H3 domain helix. Specifically, Inhibitors,Modulators,Libraries JY 1 106 was devised to reproduce the key hydrophobic side chains of Val74, Leu78 and Ile81, all of which lie on one face of the Bak BH3 helix and have been shown to be critical to mediating Baks protein protein interactions.

Our computational modeling studies suggest that JY 1 106 binds at the hydrophobic grove better of anti apoptotic pro teins such as Bcl xL and Mcl 1 and engages amino acid residues that are involved in binding to the Bak BH3 helices of pro apoptotic proteins. The control com pound JY 1 106a makes few favorable contacts leading to increased fluctuations of the binding regions of both Bcl xL and Mcl 1, confirming that the side chains attached to the trisarylamide scaffold are required for interaction with Bcl xL and Mcl 1.