Cell death plays a crucial role in physiological and pathological processes including development, aging and many diseases.Apoptosis is a mechanism in which cells undergo programmed death to maintain tissue homeostasis. Dysregulation in apoptotic pathways may lead to insufficient or premature cell death, which consequently induces numerous human diseases including cancer. Specific protein-protein interactions of Bcl-2 family proteins are principal regulatory factors for inducing apoptosis. Bcl-2 family are comprised of two categories of proteins, anti-apoptotic and pro-apoptotic. A BH3 domain of a pro-apoptotic protein adopts an a-helical structure and binds to a hydrophobic groove on the surface of an anti-apoptotic member. Considering the significance of a-helical BH3 domains for the complex formation between Bcl-2 proteins, we designed peptidomimetics of BH3 domains based on a tris-benzamide scaffold that can reproduce the spatial arrangement of key side chain functional groups of amino acids at the i, i+4, and i+7 positions of a helix representing a helical face. A series of tris-benzamides were designed and synthesized to mimic BH3 domains of pro-apoptotic Bcl-2 proteins. The resulting BH3 peptidomimetics were tested for their binding affinity to Bcl-xL and cytotoxicity to prostate cancer cell lines showing sub-micromolar affinity and growth inhibition. Leading compounds were found to induce apoptosis examined by mitochondrial membrane potential changes and flow cytometric analysis. In addition, these compounds demonstrated a capability of inhibiting tumor growth in mouse xenograft model, indicating a high potential of tris-benzamides for prostate cancer treatment.

Structure-based design of peptidomimetics of Bcl-2 proteins for inducing apoptosis in prostate cancer

247th National Meeting (2014)

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