Abstract
A series of new Smac mimetics have been designed, synthesized, and evaluated. The most potent compound 10 binds to XIAP, cIAP-1, and cIAP-2 BIR3 proteins with K(i) of 3.9, 0.37, and 0.25 nM, respectively. Compound 10 antagonizes XIAP in a cell-free functional assay and induces rapid cIAP-1 degradation in cancer cells. Compound 10 inhibits cell growth in the MDA-MB-231 cancer cell line with an IC(50) of 8.9 nM.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Alanine / analogs & derivatives*
-
Alanine / chemical synthesis
-
Alanine / pharmacology
-
Apoptosis / drug effects
-
Apoptosis Regulatory Proteins
-
Breast Neoplasms
-
Bridged Bicyclo Compounds, Heterocyclic / chemical synthesis*
-
Bridged Bicyclo Compounds, Heterocyclic / pharmacology
-
Cell Line, Tumor
-
Humans
-
Inhibitor of Apoptosis Proteins / chemical synthesis
-
Inhibitor of Apoptosis Proteins / chemistry*
-
Intracellular Signaling Peptides and Proteins / chemical synthesis*
-
Mitochondrial Proteins / chemical synthesis*
-
X-Linked Inhibitor of Apoptosis Protein / metabolism
Substances
-
Apoptosis Regulatory Proteins
-
Bridged Bicyclo Compounds, Heterocyclic
-
DIABLO protein, human
-
DM-28 compound
-
Inhibitor of Apoptosis Proteins
-
Intracellular Signaling Peptides and Proteins
-
Mitochondrial Proteins
-
X-Linked Inhibitor of Apoptosis Protein
-
Alanine