Tris-Benzamide Analogs for Inhibiting Bcl-2 Proteins in Prostate Cancer

摘要

Apoptosis is an important cellular mechanism for tissue homeostasis and aberration in the process is well documented in cancers including castration-resistant prostate cancer (CRPC) [1]. Since it is regulated by heterodimerization of Bcl-2 family proteins, disrupting such protein complexes is attractive for therapeutic intervention. Structural studies revealed that the helical BH3 domain of pro-apoptosis proteins including Bak binds to a hydrophobic pocket in anti-apoptotic proteins like Bcl-xL [2,3]. To mimic helical BH3 domain, we have reported the synthesis and biological activity of tris-benzamides which can place three functional groups corresponding to the side chains found at the i, i+4, and i+7 positions in an a-helix [4,5]. To improve the activity of tris-benzamides, we have modified them by introducing additional side chain group at either end of molecules or changing one of side chain group. This library of tris-benzamide analogs as BH3 peptidomimetics was then examined for their binding affinity to anti-apoptotic Bcl-xL protein, inhibition of cell proliferation of various prostate cancer cell lines, mechanism of action, and in vivo efficacy. We have identified several leading compounds that showed strong binding affinity as well as high metabolic stability and cell permeation. These compounds were found to be effective in inhibiting cell growth of several prostate cancer cell lines and provided evidence of inducing apoptosis. These results show a potential of BH3 mimetics in treating prostate cancer.