发明名称 |
COMPOUNDS AND METHODS FOR INDUCING APOPTOSIS IN CANCER CELLS USING A BH3 ALPHA-HELICAL MIMETIC |
摘要 |
A novel BH3 a-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 BCI-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. |
申请公布号 |
WO2012097133(A3) |
申请公布日期 |
2012.11.01 |
申请号 |
WO2012US21049 |
申请日期 |
2012.01.12 |
申请人 |
H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE, INC.;YALE UNIVERSITY;INTEZYNE TECHNOLOGIES, INC.;SEBTI, SAID M.;HAMILTON, ANDREW D.;SILL, KEVIN;CARIE, ADAM |
发明人 |
SEBTI, SAID M.;HAMILTON, ANDREW D.;SILL, KEVIN;CARIE, ADAM |
分类号 |
C07C217/22;A61K31/165;A61P35/00;C07C217/18 |
主分类号 |
C07C217/22 |
代理机构 |
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代理人 |
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