Compositions and methods for enhancing apoptosis
AssigneeGenentech, Inc.
InventorsKurt Deshayes, Wayne Fairbrother, John Flygare, Matthew C. Franklin, Saloumeh Fischer, Domagoj Vucic
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Abstract
The present invention is directed to compositions of matter useful for the enhancement of apoptosis in mammals and to methods of using those compositions of matter for the same.
Claims20
An isolated BDB oligopeptide, that specifically binds ML-IAP and releases the inhibitory effect that ML-IAP has on caspase activity.
An isolated BDB oligopeptide comprising the sequence AN2N3N4, wherein;
- N2 is Glu or Asp
- N3 is Val, Ile, Leu or (2S,3S)-3-methylpyrrolidine-2-carboxylic acid [(3S)-methyl-proline]
- N4 is homophenylalanine, 4-amino-phenylalanine, 4-phenyl-phenylalanine, 2,2-diphenylethylamine, (1S,2S)-(+)-2-amino-1-phenyl-1,3-propandiol, 3-trifluoromethylphenylethylamine, (1R,2R)-(−)-2-amino-1-phenyl-1,3-propandiol, trans-2-phenylcyclopropylamine, (1R,1S)-(+)-norephedrine, β-methylphenylethylamine, (S)-(−)-2-amino-3-phenyl-1-propanol, (R)-(−)-2-amino-1-phenylethanol, 3-ethoxyphenylethylamine, 5-bromo-2-methoxyphenylethylamine, 3-fluorophenylethylamine, (S)-(+)-α-(methoxymethyl)-phenylethylamine, 3-chlorophenylethylamine, or 2-ethoxyphenylethylamine.
An isolated BDB oligopeptide, selected from the group consisting of;
- AVGVPWKSE (SEQ ID NO:6), AEAVAWKSE (SEQ ID NO:7), ATAVIEKSE (SEQ ID NO:8), AEAVPWKSE (SEQ ID NO:9), AEVVAVKSE (SEQ ID NO:10) and AQAVAWKSE (SEQ ID NO:11).
A method of screening antagonists of IAP polypeptides comprising:
- (a) co-crystallizing the potential antagonist with the BIR domain of an ML-IAP polypeptide to form a co-crystalline structure and determining if the potential antagonist binds to said BIR domain;
- (b) determining whether said antagonist increases apoptosis in cells relative to antagonist untreated cells.
A method of screening antagonists of an ML-IAP polypeptide comprising co-crystallizing the potential antagonist with the BIR domain of an ML-IAP polypeptide to form a co-crystalline structure and determining if the potential antagonist binds to said BIR domain, and wherein binding occurs if there is at least one contact between a specific amino acid residue of a given patch and the candidate molecule that is less than or equal to 2.8 angstroms in the co-crystalline structure.
A method of screening potential antagonists of an ML-IAP polypeptide comprising:
- (a) co-crystallizing the potential antagonist with the BIR domain of an ML-IAP polypeptide to form a co-crystalline structure and determining if the potential antagonist binds to said BIR domain;
- (b) determining if said potential antagonist inhibits the binding of said ML-IAP to a caspase.
Dependencies are inferred from the claim text.