Said M. Sebti,Andrew D. Hamilton,Kevin Sill,Adam Carie
申请号：
US13940967
公开号：
US20130295185A1
申请日:
2013.07.12
申请国别(地区):
US
年份:
2013
代理人:
摘要：
A novel BH3 α-helical mimetic, BH3-M6, which binds to Bcl-XL 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-XL, 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-XL levels are more sensitive to BH3-M6-induced cell death, suggesting that this compound can overcome drug resistance due to Bcl-2 or Bcl-XL 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.
