From Wikipedia, the free encyclopedia
Experimental Drug
JHU-083
![](https://upload.wikimedia.org/wikipedia/commons/thumb/7/7c/JHU-083_structure.png/220px-JHU-083_structure.png) |
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Ethyl (2S)-2-[[(2S)-2-amino-4-methylpentanoyl]amino]-6-diazo-5-oxohexanoate
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CAS Number | |
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PubChem
CID | |
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ChemSpider | |
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ChEMBL | |
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Formula | C14H24N4O4 |
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Molar mass | 312.370 g·mol−1 |
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3D model (
JSmol) | |
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CCOC(=O)[C@H](CCC(=O)C=[N+]=[N-])NC(=O)[C@H](CC(C)C)N
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InChI=1S/C14H24N4O4/c1-4-22-14(21)12(6-5-10(19)8-17-16)18-13(20)11(15)7-9(2)3/h8-9,11-12H,4-7,15H2,1-3H3,(H,18,20)/t11-,12-/m0/s1 Key:YZRCHOFKIPHQBW-RYUDHWBXSA-N
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JHU-083 is an experimental drug which acts as a
glutaminase
inhibitor. It is a
prodrug which is cleaved in vivo to the active form
6-diazo-5-oxo-L-norleucine. It has been researched for the treatment of various neurological conditions such as
depression,
Alzheimer's disease, and
cerebral malaria,
[1]
[2]
[3] as well as
multiple sclerosis,
[4]
atherosclerosis,
[5]
hepatitis,
[6] and some forms of
cancer in which it was found to target
senescent cells.
[7]
[8]
[9]
[10]
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^ Zhu X, Nedelcovych MT, Thomas AG, Hasegawa Y, Moreno-Megui A, Coomer W, et al. (March 2019).
"JHU-083 selectively blocks glutaminase activity in brain CD11b+ cells and prevents depression-associated behaviors induced by chronic social defeat stress". Neuropsychopharmacology. 44 (4): 683–694.
doi:
10.1038/s41386-018-0177-7.
PMC
6372721.
PMID
30127344.
-
^ Hollinger KR, Zhu X, Khoury ES, Thomas AG, Liaw K, Tallon C, et al. (2020).
"Glutamine Antagonist JHU-083 Normalizes Aberrant Hippocampal Glutaminase Activity and Improves Cognition in APOE4 Mice". Journal of Alzheimer's Disease. 77 (1): 437–447.
doi:
10.3233/JAD-190588.
PMC
7678030.
PMID
32675407.
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^ Riggle BA, Sinharay S, Schreiber-Stainthorp W, Munasinghe JP, Maric D, Prchalova E, et al. (December 2018).
"MRI demonstrates glutamine antagonist-mediated reversal of cerebral malaria pathology in mice". Proceedings of the National Academy of Sciences of the United States of America. 115 (51): E12024–E12033.
Bibcode:
2018PNAS..11512024R.
doi:
10.1073/pnas.1812909115.
PMC
6304986.
PMID
30514812.
-
^ Hollinger KR, Smith MD, Kirby LA, Prchalova E, Alt J, Rais R, et al. (November 2019).
"Glutamine antagonism attenuates physical and cognitive deficits in a model of MS". Neurology. 6 (6): e609.
doi:
10.1212/NXI.0000000000000609.
PMC
6745721.
PMID
31467038.
-
^ Park HY, Kim MJ, Lee S, Jin J, Lee S, Kim JG, et al. (May 2021).
"Inhibitory Effect of a Glutamine Antagonist on Proliferation and Migration of VSMCs via Simultaneous Attenuation of Glycolysis and Oxidative Phosphorylation". International Journal of Molecular Sciences. 22 (11): 5602.
doi:
10.3390/ijms22115602.
PMC
8198131.
PMID
34070527.
-
^ Tu H, Yin X, Wen J, Wu W, Zhai B, Li J, Jiang H (December 2022). "Glutaminase 1 blockade alleviates nonalcoholic steatohepatitis via promoting proline metabolism". Biochemical and Biophysical Research Communications. 634: 1–9.
doi:
10.1016/j.bbrc.2022.10.007.
PMID
36223657.
S2CID
252733914.
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^ Hanaford AR, Alt J, Rais R, Wang SZ, Kaur H, Thorek DL, et al. (October 2019).
"Orally bioavailable glutamine antagonist prodrug JHU-083 penetrates mouse brain and suppresses the growth of MYC-driven medulloblastoma". Translational Oncology. 12 (10): 1314–1322.
doi:
10.1016/j.tranon.2019.05.013.
PMC
6657308.
PMID
31340195.
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^ Yamashita AS, da Costa Rosa M, Stumpo V, Rais R, Slusher BS, Riggins GJ (2021).
"The glutamine antagonist prodrug JHU-083 slows malignant glioma growth and disrupts mTOR signaling". Neuro-Oncology Advances. 3 (1): vdaa149.
doi:
10.1093/noajnl/vdaa149.
PMC
7920530.
PMID
33681764.
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^ Huang M, Xiong D, Pan J, Zhang Q, Sei S, Shoemaker RH, et al. (September 2022).
"Targeting Glutamine Metabolism to Enhance Immunoprevention of EGFR-Driven Lung Cancer". Advanced Science. 9 (26): e2105885.
doi:
10.1002/advs.202105885.
PMC
9475521.
PMID
35861366.
-
^ Kaushik AK, Tarangelo A, Boroughs LK, Ragavan M, Zhang Y, Wu CY, et al. (December 2022).
"In vivo characterization of glutamine metabolism identifies therapeutic targets in clear cell renal cell carcinoma". Science Advances. 8 (50): eabp8293.
Bibcode:
2022SciA....8P8293K.
doi:
10.1126/sciadv.abp8293.
PMC
9757752.
PMID
36525494.