However, many of the BH3 mimetics that potently engage the Bcl 2/Bcl xL/ Bcl w sub class of the anti apoptotic Bcl 2 proteins often only weakly inhibit members of the Mcl 1/Bfl 1 sub class. An effective BH3 mimetic should neutralize both sub classes, as this is required for apoptosis selleck chemical Imatinib to occur. We herein describe the biological characterization of our novel pan Bcl 2 inhibitor JY 1 106, which, based on a trisarylamide framework, reproduces the chemical nature and relative spatial projections of the key hydrophobic side chains on one face of the BH3 helix. JY 1 106 induces cancer cell death regard less of the Mcl 1 expression levels through intrinsic apoptosis pathways, and sensitizes tumor cells to che motherapeutic agents and to metabolic stress.

Further more, we demonstrate Inhibitors,Modulators,Libraries that JY 1 106 inhibits tumor growth in a lung cancer xenograft model, and, therefore, that helix mimicry based on a trisarylamide scaffold warrants further investigation towards the development of novel chemotherapeutics. Results Design Both faces of the BH3 helix contribute to the stabilization of the protein protein complex upon docking with the BH3 binding groove. In addition to the previously mentioned hydrophobic residues on one face of the Bak BH3 helix, Arg76 and Asp83 located on the other face of the helix are also important for binding. Thus, towards the development of potent, pan Bcl 2 antagonists, we wished to design amphipathic helix mimetics that would achieve more superior helix mimicry than ever reported before, as well as, potentially, better selectivity profiles against non Bcl 2 proteins.

We reasoned that this process would be accelerated by selecting and modifying a functional helix mimetic from the literature. Compounds Inhibitors,Modulators,Libraries based on an oligoamide foldamer strategy appeared excellent candidates, primarily owing to their straightforward chemical syntheses. A structure activity relationship analysis of the backbone of a previously reported oligoamide based Inhibitors,Modulators,Libraries helix mimetic designed to inhibit Bcl xL led to the discovery of the novel compound JY 1 106 with even greater affinity for Bcl xL. Although only the second most potent compound of the congeners synthesized, the aque ous solubility of JY 1 106 was, in our hands, Inhibitors,Modulators,Libraries greater than that of the most potent derivative, and so JY 1 106 was selected for further biological characterization.

Computational analyses of the binding of JY 1 106 to Bcl xL and Mcl 1 Molecular details of the interactions of JY 1 106 with Bcl xL and Mcl 1 were obtained by modeling inhibitor binding with these proteins based on the crystallographic orientations Inhibitors,Modulators,Libraries of the bound peptides, followed by MD simu lations. In addition, the SILCS selleck chem inhibitor methodology was applied to quantify the energetic differences associated with binding to the two proteins and between the binding of JY 1 106 and its analog JY 1 106a to the proteins.