Smac/diablo inhibitors useful for treating cancer
AssigneeThe National Institute for Biotechnology In the Negev Ltd.
InventorsVarda SHOSHAN-BARMATZ, Yakov KRELIN, Avijit PAUL
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Abstract
The present invention relates to compositions and methods for treating cancer, particularly to agents that inhibit the expression and/or activity of the protein second mitochondria-derived activator of caspase/direct inhibitor of apoptosis-binding protein with low pI (SMAC/Diablo). The inhibiting agents include RNA interference molecules silencing the expression of SMAC/Diablo and peptides modulating its interactions within the cell nucleus and mitochondria. The methods and agents of the present invention are useful in treating cancers associated with overexpression of SMAC/Diablo.
Claims23
1-65. (canceled)
A method for treating cancer associated with over-expression of second mitochondria-derived activator of caspase/direct inhibitor of apoptosis-binding protein with low pI (SMAC/Diablo) in a subject in need thereof, comprising administering to the subject an effective amount of at least one agent that inhibits the expression and/or activity of the SMAC/Diablo, wherein the agent is selected from the group consisting of an inhibitory nucleic acid, an inhibitory peptide, an inhibitory small molecule, an inhibitory aptamer, combinations thereof and a pharmaceutical composition comprising same.
An isolated SMAC/Diablo silencing molecule selected from the group consisting of:
- a silencing molecule comprising a first oligonucleotide comprising the nucleic acid sequence set forth in SEQ ID NO:12 and optionally a 3′ overhang of 1-5 nucleotides, derivatized by 2′-O-methyl (2′-O-Me) at positions 5, 10, 16, and 21 and a second oligonucleotide comprising the nucleic acid sequence set forth in SEQ ID NO:13 and optionally a 3′ overhang of 1-5 nucleotides, derivatized by 2′-O-Me at positions 6, 12 and 19;
- a silencing molecule comprising a first oligonucleotide comprising the nucleic acid sequence set forth in SEQ ID NO:12 and optionally a 3′ overhang of 1-5 nucleotides, derivatized by 2′-O-methyl (2′-O-Me) at positions 3, 6, 11 and 21, and a second oligonucleotide comprising the nucleic acid sequence set forth in SEQ ID NO:13 and optionally a 3′ overhang of 1-5 nucleotides, derivatized by 2′-O-Me at positions 6 and 1;
- a silencing molecule comprising a first oligonucleotide having the nucleic acid sequence set forth in SEQ ID NO:14 and optionally a 3′ overhang of 1-5 nucleotides and a second oligonucleotide having the nucleic acid sequence set forth in SEQ ID NO:15 and optionally a 3′ overhang of 1-5 nucleotides;
- a silencing molecule comprising a first oligonucleotide having the nucleic acid sequence set forth in SEQ ID NO:16 and optionally a 3′ overhang of 1-5 nucleotides and a second oligonucleotide having the nucleic acid sequence set forth in SEQ ID NO:17 and optionally a 3′ overhang of 1-5 nucleotides;
- and
- a silencing molecule comprising a first oligonucleotide having the nucleic acid sequence set forth in SEQ ID NO:16 and optionally a 3′ overhang of 1-5 nucleotides and a second oligonucleotide having the nucleic acid sequence set forth in SEQ ID NO:17 and optionally a 3′ overhang of 1-5 nucleotides
An isolated synthetic or recombinant peptide having an amino acid sequence at least 80% homologous to an amino acid sequence selected from the group consisting of SEQ ID NOs:46-67, an analog, derivative or a fragment thereof, wherein the peptide is capable of binding to human SMAC/Diablo.
Dependencies are inferred from the claim text.