Compounds and methods for modulating activation of NF-kB
AssigneeSignal Pharmaceuticals, LLC
InventorsAnthony M. Manning, Frank Mercurio, Sharon Amit, Yinon Ben-Neriah, Matti Davis, Ada Hatzubai, Avraham Yaron, Irit Alkalay, Aaron Ciechanover
Life of this patent
Estimating the term…
Abstract
Compositions and methods for modulating the activation of nuclear factor κB (NF-κB) are provided. The compositions comprise one or more agents that modulate ubiquitination of phosphorylated IκBα and/or IκBβ. Such compositions may be used for treating diseases associated with NF-κB activation. Modulating agents include human E3 ubiquitin ligases, antibodies thereto and variants thereof, as well as related proteins.
Claims25
An isolated polypeptide having the sequence recited in SEQ ID NO:
- 16 or a variant thereof that differs in one or more amino acid deletions, insertions or substitutions at no more than 15% of the residues in SEQ ID NO:
- 16, such that the polypeptide enhances ubiquitination of phosphorylated IκB.
An isolated polypeptide comprising a portion of a human E3 ubiquitin, ligase recited in SEQ ID NO:
- 16 or variant thereof that differs in one or more amino acid deletions, insertions, or substitutions at no more than 15% of the residues in SEQ ID NO:
- 16 wherein the portion binds to phosphorylated IκB and inhibits ubiquitination of phosphorylated IκB.
A pharmaceutical composition, comprising:
- (a) an isolated human E3 ubiquitin ligase polypeptide, wherein the polypeptide comprises a sequence recited in SEQ ID NO:
- 16 or a portion or variant thereof that differs in one or more amino acid insertions, deletions, additions or substitutions at no more than 20% of the residues in SEQ ID NO:
- 16, such that the polypeptide enhances ubiquitination of phosphorylated IκB;
- and
- (b) a physiologically acceptable carrier.
A pharmaceutical composition, comprising:
- (a) an isolated human E3 ubiquitin ligase polypeptide, wherein the polypeptide comprises a portion of a sequence recited in SEQ ID NO:
- 16, or variant thereof that differs in one or more amino acid substitutions, insertions, deletions or additions, such that the;
- polypeptide binds to phosphorylated IκB and inhibits ubiquitination of phosphorylated IκB;
- and
- (b) a physiologically acceptable carrier.
A pharmaceutical composition, comprising:
- (a) a polynucleotide encoding a human E3 ubiquitin ligase polypeptide, wherein the polypeptide comprises a sequence recited in SEQ ID NO:
- 16 or a portion or variant thereof that differs in one or more amino acid insertions, deletions, additions or substitutions at no more than 20% of the residues in SEQ ID NO:
- 16, such that the polypeptide enhances ubiquitination of phosphorylated IκB;
- and;
- (b) a physiologically acceptable carrier.
A pharmaceutical composition, comprising:
- (a) a polynucleotide encoding a human E3 ubiquitin ligase polypeptide, wherein the polypeptide comprises a portion of a sequence recited in SEQ ID NO:
- 16, or variant thereof that differs in one or more amino acid substitutions, insertions, deletions or additions, such that the polypeptide binds to phosphorylated IκB and inhibits ubiquitination of phosphorylated IκB;
- and
- (b) a physiologically acceptable carrier.
An isolated antibody, or antigen binding fragment thereof, that binds to a human E3 ubiquitin ligase sequence recited in SEQ ID NO:
- 16.
A method for screening for an agent that modulates NF-κB activity, comprising the steps of:
- (a) contacting a candidate agent with an isolated human E3 ubiquitin ligase polypeptide, wherein the polypeptide comprises a sequence recited in SEQ ID NO:
- 16 or a portion or variant thereof that differs in one or more amino acid substitutions, insertions, deletions or additions, such that the polypeptide enhances ubiquitination of phosphorylated IκB, under conditions and for a time sufficient to permit interaction between the polypeptide and candidate agent;
- and
- (b) subsequently evaluating the ability of the polypeptide to enhance ubiquitination of phosphorylated IκB, relative to a predetermined ability of the polypeptide to enhance ubiquitination of phosphorylated IκB in the absence of candidate agent;
- and therefrom identifying an agent that modulates NF-κB activity.
A method for modulating NF-κB activity in a patient, comprising administering to a patient a polypeptide comprising a β-TrCP protein (SEQ ID NO:
- 18), or a portion or variant thereof that differs in one or more amino acid insertions, deletions, additions or substitutions at no more than 20% of the residues in SEQ ID NO:
- 18, such that the polypeptide enhances ubiquitination of phosphorylated IκB, and thereby modulating NF-κB activity in the patient.
A method for treating a patient afflicted with a disorder associated with NF-κB activation, comprising administering to a patient a therapeutically effective amount of a polypeptide comprising a β-TrCP protein (SEQ ID NO:
- 18), or a portion or variant thereof that differs in one or more amino acid insertions, deletions, additions or substitutions at no more than 20% of the residues in SEQ ID NO:
- 18, such that the polypeptide enhances ubiquitination of phosphorylated IκB, and thereby treating a disorder associated with NF-κB activation.
A method for screening for an agent that modulates NF-IκB activity, comprising the steps of:
- (a) contacting a candidate agent with a polypeptide comprising a βTrCP protein (SEQ ID NO:
- 18), or a portion or variant thereof that differs in one or more amino acid insertions, deletions, additions or substitutions at no more than 20% of the residues in SEQ ID NO:
- 18, such that the polypeptide enhances ubiquitination of phosphorylated IκB, under conditions and for a time sufficient to permit interaction between the polypeptide and candidate agent;
- and
- (b) subsequently evaluating the ability of the polypeptide to enhance ubiquitination of phosphorylated I κB, relative to a predetermined ability of the polypeptide to enhance ubiquitination of phosphorylated IκB in the absence of candidate agent;
- and there from identifying an agent that modulates NF-κB activity.
Dependencies are inferred from the claim text.