Methods of treatment using modulators of SIRT2
The instant application describes novel compounds that modulate (in particular, inhibit) Sirt2, with structures according to Formulas (1) and (2) provided herein. The invention is also directed to pharmaceutical compositions thereof, methods of treatment (i.e., cancer and neurodegenerative disease) by administration of the modulating compounds, assay methods for finding modulators of Sirt2, and kits for practicing the assay method.
1. A method for treating a subject suffering from cancer, the method comprising administering to said subject a modulator of Sirt2 in a pharmaceutically effective amount for treating said cancer, the modulator of Sirt2 having the following chemical structure:
wherein R 1 is a hydrocarbon group having at least five carbon atoms connected by carbon-carbon bonds, wherein said hydrocarbon group optionally includes one heteroatom group selected from —O—, —NR 5 —, and —S— that interrupts a carbon-carbon bond of said hydrocarbon group, and wherein one or more hydrogen atoms in said hydrocarbon group are optionally replaced with fluoro atoms, wherein R 5 is a hydrogen atom or a hydrocarbon group;
R 2 is selected from a hydrogen atom or a hydrocarbon group;
R 3 and R 4 are independently selected from hydrogen atom and hydrocarbon groups R, wherein said hydrocarbon groups R are optionally substituted with one or more heteroatoms; and
X 1 , X 2 , and X 3 are independently selected from —(CH 2 ) n —, —NR 5 —, —O—, —S—, or a bond, wherein n represents 1, 2, or 3, and at least one of X 1 , X 2 , and X 3 is a —CH 2 — group.
2. The method of claim 1 , wherein the hydrocarbon group for R 1 has at least five carbon atoms connected by carbon-carbon bonds in the absence of heteroatom interruption, except that one or more hydrogen atoms are optionally replaced with fluoro atoms.
3. The method of claim 1 , wherein said modulator of Sirt2 is an inhibitor of Sirt2.
4. The method of claim 3 , wherein said inhibitor of Sirt2 is a selective inhibitor of Sirt2.
5. The method of claim 1 , wherein at least one of R 3 and R 4 is comprised of at least one amino acid residue.
6. The method of claim 1 , wherein at least one of R 3 and R 4 is comprised of a monocyclic unsaturated ring.
7. The method of claim 1 , wherein each of R 3 and R 4 is comprised of a monocyclic unsaturated ring.
8. The method of claim 1 , wherein said modulator of Sirt2 has the following chemical structure:
wherein R 1 is a hydrocarbon group having at least five carbon atoms connected by carbon-carbon bonds, wherein said hydrocarbon group optionally includes one heteroatom group selected from —O—, —NR 5 —, and —S— that interrupts a carbon-carbon bond of said hydrocarbon group, and wherein one or more hydrogen atoms in said hydrocarbon group are optionally replaced with fluoro atoms, wherein R 5 is a hydrogen atom or a hydrocarbon group;
R 2 is selected from a hydrogen atom or a hydrocarbon group;
R 6 and R 7 are independently selected from hydrogen atom, unsubstituted hydrocarbon groups having up to six carbon atoms, alkoxy groups —OR, amide groups —NR′C(O)R or —C(O)NR′R, ketone groups —C(O)R, ester groups —C(O)OR or —OC(O)R, carbamate groups —OC(O)NR′R or —NR′C(O)OR, and urea groups —NR′C(O)NR, wherein R is a hydrocarbon group having up to six carbon atoms, and R′ is a hydrogen atom or a hydrocarbon group having up to six carbon atoms;
X 1 , X 2 , and X 3 are independently selected from —(CH 2 ) n —, —NR 5 —, —O—, —S—, or a bond, wherein n represents 1, 2, or 3, and at least one of X 1 , X 2 , and X 3 is a —CH 2 — group; and
Y 1 and Y 2 are independently selected from —O—, —NR 5 —, and —S— groups.