JHU-083

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JHU-083
Identifiers
  • Ethyl (2S)-2-[[(2S)-2-amino-4-methylpentanoyl]amino]-6-diazo-5-oxohexanoate
CAS Number
PubChem CID
ChemSpider
ChEMBL
Chemical and physical data
FormulaC14H24N4O4
Molar mass312.370 g·mol−1
3D model (JSmol)
  • CCOC(=O)[C@H](CCC(=O)C=[N+]=[N-])NC(=O)[C@H](CC(C)C)N
  • 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

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]

References

  1. ^ 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.
  2. ^ 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.
  3. ^ 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.
  4. ^ 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.
  5. ^ 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.
  6. ^ 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.
  7. ^ 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.
  8. ^ 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.
  9. ^ 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.
  10. ^ 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.
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