JHU-083: Difference between revisions

JHU-083
Identifiers
	IUPAC name ethyl (2S)-2-[[(2S)-2-amino-4-methylpentanoyl]amino]-6-diazo-5-oxohexanoate;
CAS Number	1998725-11-3;
PubChem CID	137283416;
Chemical and physical data
Formula	C14H24N4O4
Molar mass	312.370 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES CCOC(=O)[C@H](CCC(=O)C=[N+]=[N-])NC(=O)[C@H](CC(C)C)N;
	InChI 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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Revision as of 22:59, 16 August 2023

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 selectively target senescent cells.^[7]^[8]^[9]^[10]

References

^ 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. JHU-083 selectively blocks glutaminase activity in brain CD11b+ cells and prevents depression-associated behaviors induced by chronic social defeat stress. Neuropsychopharmacology. 2019 Mar;44(4):683-694. doi:10.1038/s41386-018-0177-7 PMID 30127344
^ Hollinger KR, Zhu X, Khoury ES, Thomas AG, Liaw K, Tallon C, Wu Y, Prchalova E, Kamiya A, Rojas C, Kannan S, Slusher BS. Glutamine Antagonist JHU-083 Normalizes Aberrant Hippocampal Glutaminase Activity and Improves Cognition in APOE4 Mice. J Alzheimers Dis. 2020;77(1):437-447. doi:10.3233/JAD-190588 PMID 32675407
^ Riggle BA, Sinharay S, Schreiber-Stainthorp W, Munasinghe JP, Maric D, Prchalova E, Slusher BS, Powell JD, Miller LH, Pierce SK, Hammoud DA. MRI demonstrates glutamine antagonist-mediated reversal of cerebral malaria pathology in mice. Proc Natl Acad Sci USA. 2018 Dec 18;115(51):E12024-E12033. doi:10.1073/pnas.1812909115 PMID 30514812
^ Hollinger KR, Smith MD, Kirby LA, Prchalova E, Alt J, Rais R, Calabresi PA, Slusher BS. Glutamine antagonism attenuates physical and cognitive deficits in a model of MS. Neurol Neuroimmunol Neuroinflamm. 2019 Aug 29;6(6):e609. doi:10.1212/NXI.0000000000000609 PMID 31467038
^ Park HY, Kim MJ, Lee S, Jin J, Lee S, Kim JG, Choi YK, Park KG. Inhibitory Effect of a Glutamine Antagonist on Proliferation and Migration of VSMCs via Simultaneous Attenuation of Glycolysis and Oxidative Phosphorylation. Int J Mol Sci. 2021 May 25;22(11):5602. doi:10.3390/ijms22115602 PMID 34070527
^ Tu H, Yin X, Wen J, Wu W, Zhai B, Li J, Jiang H. Glutaminase 1 blockade alleviates nonalcoholic steatohepatitis via promoting proline metabolism. Biochem Biophys Res Commun. 2022 Dec 17;634:1-9. doi:10.1016/j.bbrc.2022.10.007 PMID 36223657
^ Hanaford AR, Alt J, Rais R, Wang SZ, Kaur H, Thorek DLJ, Eberhart CG, Slusher BS, Martin AM, Raabe EH. Orally bioavailable glutamine antagonist prodrug JHU-083 penetrates mouse brain and suppresses the growth of MYC-driven medulloblastoma. Transl Oncol. 2019 Oct;12(10):1314-1322. doi:10.1016/j.tranon.2019.05.013 PMID 31340195
^ 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. Neurooncol Adv. 2020 Oct 29;3(1):vdaa149. doi:10.1093/noajnl/vdaa149 PMID 33681764
^ Huang M, Xiong D, Pan J, Zhang Q, Sei S, Shoemaker RH, Lubet RA, Montuenga LM, Wang Y, Slusher BS, You M. Targeting Glutamine Metabolism to Enhance Immunoprevention of EGFR-Driven Lung Cancer. Adv Sci (Weinh). 2022 Sep;9(26):e2105885. doi:10.1002/advs.202105885 PMID 35861366
^ 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. In vivo characterization of glutamine metabolism identifies therapeutic targets in clear cell renal cell carcinoma. Sci Adv. 2022 Dec 16;8(50):eabp8293. doi:10.1126/sciadv.abp8293 PMID 36525494

[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. JHU-083 selectively blocks glutaminase activity in brain CD11b+ cells and prevents depression-associated behaviors induced by chronic social defeat stress. Neuropsychopharmacology. 2019 Mar;44(4):683-694. doi:10.1038/s41386-018-0177-7 PMID 30127344

[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. Glutamine Antagonist JHU-083 Normalizes Aberrant Hippocampal Glutaminase Activity and Improves Cognition in APOE4 Mice. J Alzheimers Dis. 2020;77(1):437-447. doi:10.3233/JAD-190588 PMID 32675407

[3] Riggle BA, Sinharay S, Schreiber-Stainthorp W, Munasinghe JP, Maric D, Prchalova E, Slusher BS, Powell JD, Miller LH, Pierce SK, Hammoud DA. MRI demonstrates glutamine antagonist-mediated reversal of cerebral malaria pathology in mice. Proc Natl Acad Sci USA. 2018 Dec 18;115(51):E12024-E12033. doi:10.1073/pnas.1812909115 PMID 30514812

[4] Hollinger KR, Smith MD, Kirby LA, Prchalova E, Alt J, Rais R, Calabresi PA, Slusher BS. Glutamine antagonism attenuates physical and cognitive deficits in a model of MS. Neurol Neuroimmunol Neuroinflamm. 2019 Aug 29;6(6):e609. doi:10.1212/NXI.0000000000000609 PMID 31467038

[5] Park HY, Kim MJ, Lee S, Jin J, Lee S, Kim JG, Choi YK, Park KG. Inhibitory Effect of a Glutamine Antagonist on Proliferation and Migration of VSMCs via Simultaneous Attenuation of Glycolysis and Oxidative Phosphorylation. Int J Mol Sci. 2021 May 25;22(11):5602. doi:10.3390/ijms22115602 PMID 34070527

[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. Biochem Biophys Res Commun. 2022 Dec 17;634:1-9. doi:10.1016/j.bbrc.2022.10.007 PMID 36223657

[7] Hanaford AR, Alt J, Rais R, Wang SZ, Kaur H, Thorek DLJ, Eberhart CG, Slusher BS, Martin AM, Raabe EH. Orally bioavailable glutamine antagonist prodrug JHU-083 penetrates mouse brain and suppresses the growth of MYC-driven medulloblastoma. Transl Oncol. 2019 Oct;12(10):1314-1322. doi:10.1016/j.tranon.2019.05.013 PMID 31340195

[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. Neurooncol Adv. 2020 Oct 29;3(1):vdaa149. doi:10.1093/noajnl/vdaa149 PMID 33681764

[9] Huang M, Xiong D, Pan J, Zhang Q, Sei S, Shoemaker RH, Lubet RA, Montuenga LM, Wang Y, Slusher BS, You M. Targeting Glutamine Metabolism to Enhance Immunoprevention of EGFR-Driven Lung Cancer. Adv Sci (Weinh). 2022 Sep;9(26):e2105885. doi:10.1002/advs.202105885 PMID 35861366

[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. In vivo characterization of glutamine metabolism identifies therapeutic targets in clear cell renal cell carcinoma. Sci Adv. 2022 Dec 16;8(50):eabp8293. doi:10.1126/sciadv.abp8293 PMID 36525494

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