Methods for inhibiting deacetylase activity
A method for identifying a compound that inhibits the NAD + -dependent deacetylase activity of a SIR2 protein is disclosed. These compounds are useful for the treatment of cancers and other diseases, through the activation of silenced genes, through the promotion of apoptosis in cancerous cells, and through the inhibition of transcriptional repressor activity in oncogenes.
1. A method for treating lymphoma, comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound of Formula II:
wherein
R a is a member selected from the group consisting of hydrogen, C 1-6 alkyl, aryl, —OR e , —NR e R e , —CO 2 R e , —C(O)R e , —C(O)NR e R e , —CN, —NO 2 and halogen;
R b is:
X a is a member selected from the group consisting of O, S and NR e ;
R c is a member selected from the group consisting of hydrogen, C 1-6 alkyl and aryl optionally substituted with a member selected from the group consisting of hydrogen, C 1-6 alkyl, aryl, —OR e , —NR e R e , —CN, —NO 2 and halogen; and
each instance of R e is independently a member selected from the group consisting of hydrogen and C 1-6 alkyl.
2. The method of claim 1 , wherein said method is for the treatment of a B-cell-derived non-Hodgkin lymphoma or a diffuse large B-cell lymphoma.
3. The method of claim 1 , wherein said compound has the formula:
4. The method of claim 1 , wherein said compound is administered with an antineoplastic agent.
5. The method of claim 4 , wherein said antineoplastic agent is a member selected from the group consisting of antimetabolites, antifolates and other inhibitors of DNA synthesis, antisense oligonucleotides, biological response modifiers, DNA-alkylating agents, DNA intercalators, DNA repair agents, growth factor receptor kinase inhibitors, hormone agents, immunoconjugates, microtubule disruptors and topoisomerase I/II inhibitors.
6. A method of claim 5 , wherein said antineoplastic agent is a member selected from the group consisting of cyclophosphamide, triethylenephosphoramide, triethylenethiophosphoramide, BCNU, bleomycin, busulfan, chlorambucil, cytarabine, dactinomycin, daunorubicin, docetaxol, doxorubicin, epirubicin, estramustine, dacarbazine, etoposide, fluorouracil, gemcitabine, ifosfamide, methotrexate, mitomycin, mitoxantrone, paclitaxel, procarbazine, temozolomide, teniposide, thioguanine, uracil mustard, vinblastine, vincristine, vinorelbine and vindesine.
7. The method of claim 6 , wherein said antineoplastic agent is administered after said compound.
8. The method of claim 6 , wherein said antineoplastic agent is administered simultaneously with said compound.
9. The method of claim 6 , wherein said antineoplastic agent is administered prior to said compound.
10. The method of claim 1 , wherein said lymphoma has metastasized.