JHU-083 explained

Drug Name:JHU-083
C:14
H:24
N:4
O:4
Iupac Name:Ethyl (2S)-2-(2S)-2-amino-4-methylpentanoylamino]-6-diazo-5-oxohexanoate
Cas Number:1998725-11-3
Chemspiderid:76769879
Pubchem:137283416
Chembl:3925599
Smiles:CCOC(=O)[C@H](CCC(=O)C=[N+]=[N-])NC(=O)[C@H](CC(C)C)N
Stdinchi: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
Stdinchikey: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]

Notes and References

  1. Zhu X, Nedelcovych MT, Thomas AG, Hasegawa Y, Moreno-Megui A, Coomer W, Vohra V, Saito A, Perez G, Wu Y, Alt J, Prchalova E, Tenora L, Majer P, Rais R, Rojas C, Slusher BS, Kamiya A . 6 . 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 . March 2019 . 10.1038/s41386-018-0177-7 . 30127344 . 6372721 .
  2. Hollinger KR, Zhu X, Khoury ES, Thomas AG, Liaw K, Tallon C, Wu Y, Prchalova E, Kamiya A, Rojas C, Kannan S, Slusher BS . 6 . Glutamine Antagonist JHU-083 Normalizes Aberrant Hippocampal Glutaminase Activity and Improves Cognition in APOE4 Mice . Journal of Alzheimer's Disease . 2020 . 77 . 1 . 437–447 . 10.3233/JAD-190588 . 32675407 . 7678030 .
  3. Riggle BA, Sinharay S, Schreiber-Stainthorp W, Munasinghe JP, Maric D, Prchalova E, Slusher BS, Powell JD, Miller LH, Pierce SK, Hammoud DA . 6 . 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 . December 2018 . 10.1073/pnas.1812909115 . 30514812 . 6304986 . 2018PNAS..11512024R . free .
  4. Hollinger KR, Smith MD, Kirby LA, Prchalova E, Alt J, Rais R, Calabresi PA, Slusher BS . 6 . Glutamine antagonism attenuates physical and cognitive deficits in a model of MS . Neurology . 6 . 6 . November 2019 . e609 . 10.1212/NXI.0000000000000609 . 31467038 . 6745721 .
  5. Park HY, Kim MJ, Lee S, Jin J, Lee S, Kim JG, Choi YK, Park KG . 6 . 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 . May 2021 . 5602 . 10.3390/ijms22115602 . 34070527 . 8198131 . free .
  6. Tu H, Yin X, Wen J, Wu W, Zhai B, Li J, Jiang H . Glutaminase 1 blockade alleviates nonalcoholic steatohepatitis via promoting proline metabolism . Biochemical and Biophysical Research Communications . 634 . 1–9 . December 2022 . 10.1016/j.bbrc.2022.10.007 . 36223657 . 252733914 .
  7. Hanaford AR, Alt J, Rais R, Wang SZ, Kaur H, Thorek DL, Eberhart CG, Slusher BS, Martin AM, Raabe EH . 6 . Orally bioavailable glutamine antagonist prodrug JHU-083 penetrates mouse brain and suppresses the growth of MYC-driven medulloblastoma . Translational Oncology . 12 . 10 . 1314–1322 . October 2019 . 10.1016/j.tranon.2019.05.013 . 31340195 . 6657308 .
  8. Yamashita AS, da Costa Rosa M, Stumpo V, Rais R, Slusher BS, Riggins GJ . The glutamine antagonist prodrug JHU-083 slows malignant glioma growth and disrupts mTOR signaling . Neuro-Oncology Advances . 2021 . 3 . 1 . vdaa149 . 10.1093/noajnl/vdaa149 . 33681764 . 7920530 .
  9. Huang M, Xiong D, Pan J, Zhang Q, Sei S, Shoemaker RH, Lubet RA, Montuenga LM, Wang Y, Slusher BS, You M . 6 . Targeting Glutamine Metabolism to Enhance Immunoprevention of EGFR-Driven Lung Cancer . Advanced Science . 9 . 26 . e2105885 . September 2022 . 10.1002/advs.202105885 . 35861366 . 9475521 .
  10. Kaushik AK, Tarangelo A, Boroughs LK, Ragavan M, Zhang Y, Wu CY, Li X, Ahumada K, Chiang JC, Tcheuyap VT, Saatchi F, Do QN, Yong C, Rosales T, Stevens C, Rao AD, Faubert B, Pachnis P, Zacharias LG, Vu H, Cai F, Mathews TP, Genovese G, Slusher BS, Kapur P, Sun X, Merritt M, Brugarolas J, DeBerardinis RJ . 6 . In vivo characterization of glutamine metabolism identifies therapeutic targets in clear cell renal cell carcinoma . Science Advances . 8 . 50 . eabp8293 . December 2022 . 10.1126/sciadv.abp8293 . 36525494 . 9757752 . 2022SciA....8P8293K .

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