COMPOUNDS AND METHODS FOR INDUCING APOPTOSIS IN CANCER CELLS USING A BH3 ALPHA-HELICAL MIMETIC

摘要

A novel BH3 α-helical mimetic, BH3-M6, which binds to Bcl-X_L and prevents its binding to fluorescently-labeled Bak-BH3 peptide in vitro with an IC₅₀ value of 734 nM is presented herein. BH3-M6 is a pan-Bcl-2 antagonist that inhibits the binding of Bcl-X_L, Bcl-2 and Mcl-1 to multi-domain Bax or Bak, or BH3-only Bim or Bad in a cell-free system and in intact human cancer cells, freeing up pro-apoptotic proteins to induce apoptosis. BH3-M6-induced apoptosis is caspase- and Bax- dependent. Furthermore, human cancer cells with high Bcl-2 or Bcl-X_L levels are more sensitive to BH3-M6-induced cell death, suggesting that this compound can overcome drug resistance due to Bcl-2 or BCI-X_L overexpression. The pan-Bcl-2 inhibitor BH3-M6 may be encapsulated in a micelle to provide a more bioavailable therapeutic agent. Specifically, the BH3-M6 compound may be encapsulated within a micelle comprising a multiblock copolymer according to the methods described herein.