Isociatrate dehydrogenase and uses therof

• US 20080300208A1
• Filed: 02/07/2008
• Published: 12/04/2008
• Est. Priority Date: 07/11/2002
• Status: Abandoned Application

• Current Assignee: Quark Pharmaceuticals, Inc
• Original Assignee: Quark Pharmaceuticals, Inc
• Inventors: Maya, Ruth, Einat, Paz, Deiss, Louis
• Application Number:
  US12/069,188
• Publication Number:
  US 20080300208A1
• Time in Patent Office: Days
• US Class Current: 514/44
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: C07K 16/40 against enzymes

Abstract

The present invention discloses uses for the IDH gene and/or polypeptide and/or modulators thereof in the diagnosis and treatment of apoptosis-related diseases.

Claims

1. A method for treating a subject having an apoptosis-related disease comprising administering to said subject a therapeutically effective amount of an inhibitor of an isocitrate dehydrogenase (IDH) polypeptide, wherein the IDH polypeptide has an amino acid sequence as set forth in SEQ ID NO:

2 or SEQ ID NO;

4 or has a sequence which is modified therefrom while retaining the biological properties of IDH, in a dosage sufficient to inhibit expression of the IDH polypeptide so as to thereby treat the subject.

2. A method according to claim 1, wherein the inhibitor is administered in conjunction with a chemotherapeutic agent.

4. A method according to claim 1, wherein the inhibitor is a chemical molecule selected from the group consisting of 2-(4-bromo-2,3-dioxobutylthio)-1, N6-ethenoadenosine 2′

,5′

-bisphosphate, NADP oxoglutatrate, o-(carboxymethyl)oxalohydroxamate, oxalylglycine, 3-bromo-2-ketoglutarate, beta-mercapto-alpha-ketoglutarate, beta-methylmercapto-alpha-ketoglutarate, beta-methylmercapto-alpha-hydroxyglutarate, adriamycin and alpha-methylisocitrate.

5. A method according to claim 1, wherein the inhibitor is an AS fragment comprising consecutive nucleotides having a sequence as set forth in SEQ ID NO:

5.

6. A method according to claim 1, wherein the apoptosis-related disease is a cancer.

3. (canceled)

7. A method for potentiating a chemotherapeutic treatment of a subject having an apoptosis-related disease comprising administering to said subject a therapeutically effective amount of an inhibitor of a human isocitrate dehydrogenase (IDH) polypeptide in conjunction with a chemotherapeutic agent so as to thereby treat the subject;

wherein the IDH polypeptide has an amino acid sequence as set forth in SEQ ID NO;

2 or SEQ ID NO;

4 or has a sequence which is modified therefrom while retaining the biological properties of IDH.

9. A method according to claim 7, wherein the inhibitor is a chemical molecule selected from the group consisting of 2-(4-bromo-2,3-dioxobutylthio)-1, N6-ethenoadenosine 2′

,5′

-bisphosphate, NADP oxoglutatrate, o-(carboxymethyl)oxalohydroxamate, oxalylglycine, 3-bromo-2-ketoglutarate, beta-mercapto-alpha-ketoglutarate, beta-methylmercapto-alpha-ketoglutarate, beta-methylmercapto-alpha-hydroxyglutarate, adriamycin and alpha-methylisocitrate.

10. A method according to claim 7, wherein the inhibitor is an AS fragment comprising consecutive nucleotides having the a sequence as set forth in SEQ ID NO:

5.

11. A method according to claim 7, wherein the apoptosis-related disease is a cancer.

8. (canceled)

12. An antisense oligonucleotide capable of inhibiting the expression of the IDH polypeptide, having a sequence as set forth in SEQ ID NO:

5.

13. An expression vector comprising a nucleic acid encoding the antisense oligonucleotide of claim 12.

14-24. -24. (canceled)

25. A method of sensitizing a cancerous cell to apoptosis comprising the step of contacting the cell with an inhibitor of isocitrate dehydrogenase (IDH).

26. The method according to claim 25, wherein the inhibitor of isocitrate dehydrogenase (IDH) comprises an siRNA.

27. The method according to claim 25, wherein the inhibitor of isocitrate dehydrogenase (IDH) comprises an antisense oligonucleotide.

28. The method according to claim 25, wherein the apoptosis is Fas-induced or chemo-induced apoptosis.