Methods and compositions for treating metabolic reprogramming disorders
The disclosure provides methods of treating a condition, disease, or disorder in a subject that involves metabolically reprogrammed cells whose activation, function, growth, proliferation, or survival depends on increased activity of at least one metabolic pathway selected from the group consisting of glutamine metabolism, glycolysis, and fatty acid synthesis, comprising administering to the subject a compound having formula (I): and the pharmaceutically acceptable salts thereof, wherein R 1 , R 2 , R 2 ′, and X are as defined as set forth in the specification. Compounds having formula (I) are prodrugs that release glutamine analogs, e.g., 6-diazo-5-oxo-L-norleucine (DON).
1. A method for treating a condition, disease, or disorder in a subject, the method comprising administering to the subject in need thereof a compound having formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
X is —CH 2 —;
R 1 is selected from the group consisting of C 1-6 alkyl and substituted C 1-6 alkyl;
R 2 is an amino acid or an N-substituted amino acid; and
R 2 ′ is selected from the group consisting of H, C 1 -C 6 alkyl, and substituted C 1 -C 6 alkyl; and
a metabolic reprogramming agent selected from the group consisting of 2-deoxy-D-glucose and metformin;
wherein the condition, disease, or disorder is selected from the group consisting of acute respiratory distress syndrome, allograft rejection during cell, tissue, or organ transplantation, Alzheimer's disease, amyotrophic lateral sclerosis, arthritis, asthma, lupus, Parkinson's disease, and pulmonary fibrosis.
2. The method of claim 1 , wherein R 1 is selected from the group consisting of methyl, ethyl, and isopropyl.
3. The method claim 1 , wherein R 2 is an amino acid.
4. The method claim 1 , wherein R 2 is a N-acyl amino acid.
5. The method of claim 4 , wherein the amino acid is tryptophan.
6. The method of claim 1 , wherein the compound having formula (I) is a compound having formula (IIA):
wherein:
R 1 is C 1-6 alkyl;
R 11 is selected from the group consisting of H, methyl, isopropyl, sec-butyl, CH 2 CH(CH 3 ) 2 , benzyl, p-hydroxybenzyl CH 2 OH, CH(OH)CH 3 , CH 2 -3-indoyl, CH 2 COOH, CH 2 CH 2 COOH, —CH 2 C(O)NH 2 , CH 2 CH 2 C(O)NH 2 , CH 2 SH, CH 2 CH 2 SCH 3 , (CH 2 ) 4 NH 2 , (CH 2 ) 3 NHC(═NH)NH 2 , and CH 2 -3-imidazoyl;
R 12 is selected from the group consisting of H, C 1-4 alkyl, and —C(═O)R 13 ; and
R 13 is C 1-4 alkyl.
7. The method of claim 6 , wherein:
R 1 is C 1-4 alkyl;
R 11 is selected from the group consisting of isopropyl, sec-butyl, CH 2 CH(CH 3 ) 2 , and CH 2 -3-indoyl;
R 12 is selected from the group consisting of H and —C(═O)R 13 ; and
R 13 is C 1-4 alkyl.
8. The method of claim 1 , wherein the compound of formula (I) is selected from the group consisting of:
9. The method of claim 8 , wherein the compound is:
10. The method of claim 1 , wherein the at least one metabolic reprogramming agent that decreases glycolysis is 2-deoxy-D-glucose.
11. The method of claim 1 , wherein the condition, disease, or disorder is acute respiratory distress syndrome.
12. The method of claim 1 , wherein the condition, disease, or disorder is allograft rejection during cell, tissue, or organ transplantation.
13. The method of claim 1 , wherein the condition, disease, or disorder is Alzheimer's disease.
14. The method of claim 1 , wherein the condition, disease, or disorder is amyotrophic lateral sclerosis.
15. The method of claim 1 , wherein the condition, disease, or disorder is arthritis.
16. The method of claim 1 , wherein the condition, disease, or disorder is asthma.
17. The method of claim 1 , wherein the condition, disease, or disorder is lupus.
18. The method of claim 1 , wherein the condition, disease, or disorder is Parkinson's disease.
19. The method of claim 1 , wherein the condition, disease, or disorder is pulmonary fibrosis.