AKV9, Protein Aggregation Degrader
Inhibition of amyloid beta oligomer accumulation by NU-9: a unifying mechanism for the treatment of neurodegenerative diseases.
Johnson E. A, Nowar R, Viola KL, Huang W, Zhou S, Bicca MA, Zhu W, Kranz DL, Klein WL, Silverman RB. Proc. Natl. Acad. Sci. USA, 2025; 122(10): e2402117122.
Identification of a glia-associated amyloid β oligomer subtype and the rescue from reactive astrogliosis by inhibitor NU-9.
Kranz DL, de leon Velez O, Ulupinar E, Ozdinler PH, Silverman RB, Klein WL. Alzheimer’s Dement. 2025; 21: e70968.
Proteomic analysis reveals early pathological defects in corticospinal motor neurons of a spastin model of hereditary spastic paraplegia, which are improved by NU-9 treatment.
Gautam M, Priego M, Quintanilla C, Kashow O, Cho BK, Goo Y, Silverman RB, Morfini G, Baas PW, Ozdinler PH. Neurobiol. Disease 2026; 227: 107494.
Improving mitochondria and ER stability helps eliminate upper motor neuron degeneration that occurs due to mSOD1 toxicity and TDP-43 pathology
Genç B, Gautam M, Gözütok Ö, Dervishi I, Sanchez S, Goshu GM, Koçak N, Xie E, Silverman RB, Özdinler PH. Improving mitochondria and ER stability helps eliminate upper motor neuron degeneration that occurs due to mSOD1 toxicity and TDP-43 pathology. Clin Transl Med. 2021;11(2):e336.
Chiral cyclohexane 1,3-diones as inhibitors of mutant SOD1- dependent protein aggregation for the treatment of ALS
Zhang Y, Benmohamed R, Zhang W, Kim J, Edgerly CK, Zhu Y, Morimoto RI, Ferrante RJ, Kirsch DR, Silverman RB. Chiral cyclohexane 1,3-diones as inhibitors of mutant SOD1-dependent protein aggregation for the treatment of ALS. ACS Med Chem Lett. 2012; 3(7):584-587.
NU‑9 improves health of hSOD1G93A mouse upper motor neurons in vitro, especially in combination with riluzole or edaravone
Genç B., Gautam, M., Helmold, B. R., Koçak, N., Günay, A., Goshu, G. M., Silverman, R. B., & Hande Özdinler, P. NU-9 improves health of hSOD1G93A mouse upper motor neurons in vitro, especially in combination with riluzole or edaravone. Sci Rep. 2022; 12(1), 5383.
Mitochondria, ER, and nuclear membrane defects reveal early mechanisms for upper motor neuron vulnerability with respect to TDP‑43 pathology
Gautam M, Jara JH, Kocak N, Rylaarsdam LE, Kim KD, Bigio EH, Hande Özdinler P. Mitochondria, ER, and nuclear membrane defects reveal early mechanisms for upper motor neuron vulnerability with respect to TDP-43 pathology. Acta Neuropathol. 2019;137(1):47-69.
Incorporating upper motor neuron health in ALS drug discovery.
Dervishi I, Özdinler PH. Incorporating upper motor neuron health in ALS drug discovery. Drug Discov Today. 2018 Mar;23(3):696-703.
Apical dendrite degeneration, a novel cellular pathology for Betz cells in ALS
Genç B, Jara JH, Lagrimas AK, Pytel P, Roos RP, Mesulam MM, Geula C, Bigio EH, Özdinler PH. Apical dendrite degeneration, a novel cellular pathology for Betz cells in ALS. Sci Rep. 2017;7:41765.
Pathophysiological and diagnostic implications of cortical dysfunction in ALS
Geevasinga N, Menon P, Özdinler PH, Kiernan MC, Vucic S. Pathophysiological and diagnostic implications of cortical dysfunction in ALS. Nat Rev Neurol. 2016;12(11):651-661.
Treatment of amyotrophic lateral sclerosis: lessons learned from many failures
Özdinler PH, Silverman RB. Treatment of amyotrophic lateral sclerosis: lessons learned from many failures. ACS Med Chem Lett. 2014;5(11):1179-81.
Moving forward in clinical trials for ALS: motor neurons lead the way please
Genç B, Özdinler PH. Moving forward in clinical trials for ALS: motor neurons lead the way please. Drug Discov Today. 2014 Apr;19(4):441-9.
eGFP expression under UCHL1 promoter genetically labels corticospinal neurons and a subpopulation of degeneration-resistant spinal motor neurons in an ALS mouse model
Yasvoina MV, Genç B, Jara JH, Sheets PL, Quinlan KA, Milosevic A, Shepherd GM, Heckman CJ, Özdinler PH. eGFP expression under UCHL1 promoter genetically labels corticospinal motor neurons and a subpopulation of degeneration-resistant spinal motor neurons in an ALS mouse model. J Neurosci. 2013 May 1;33(18):7890-904.
Neuronal Nitric Oxide Synthase Inhibitors
A small peptide increases drug delivery in human melanoma cells.
Tong S, Darwish S, Ariani HH, Lozada KA, Salehi D, Silverman RB, Kaur K, Yang S. Pharmaceutics, 2022; 14: 1026.
Potent, selective, and membrane permeable 2-amino-4-substituted pyridine-based neuronal nitric oxide synthase inhibitors.
Vasu D, Do HT, Li H, Hardy CD, Poulos TL, Silverman RB. J. Med. Chem. 2023; 66: 9934-9953.
Crosstalk between nNOS/NO and COX-2 enhances interferon-gamma-stimulated melanoma progression.
Patel A, Tong S, Roosan MR, Syed B, Awasthi A, Silverman RB, Yang S. Cancers 2025; 17(3): 477.
Targeting neuronal nitric oxide synthase (nNOS) as a novel approach to enhancing anti-melanoma activity of immune checkpoint inhibitors.
Patel A, Tong S, Lozada K, Awasthi A, Silverman RB, Totonchy J, Yang S. Pharmaceutics 2025; 17(6): 691.
New inhibitors of neuronal nitric oxide synthase for the treatment of melanoma.
Awasthi A, Patel A, Li H, Kang KM, Hardy CD, Ansari A, Nowar RM, Hasan E, Yang S, Poulos TL, Silverman RB. J. Med. Chem. 2026; 69: 2310-2329.
Potent, selective, and brain penetrant ether-linked 2-aminopyridine inhibitors of human neuronal nitric oxide synthase with excellent oral bioavailability.
Ansari A, Chrzanowski RT, Li H, Hardy CD, Awasthi A, Poulos TL, Silverman RB. J. Med. Chem. 2026; 69: 3506-3518.
Selective neuronal nitric oxide synthase inhibitors for prevention of cerebral palsy
Ji H, Tan S, Igarashi J, Li H, Derrick M, Martásek P, Roman LJ, Vásquez-Vivar J, Poulos TL, Silverman RB. Selective neuronal nitric oxide synthase inhibitors and the prevention of cerebral palsy. Ann Neurol. 2009;65(2):209-17.
Inhibition of interferon-gamma-stimulated melanoma progression by targeting neuronal nitric oxide synthase (nNOS)
Tong S, Cinelli MA, El-Sayed NS, Huang H, Patel A, Silverman RB, Yang S. Inhibition of interferon-gamma-stimulated melanoma progression by targeting neuronal nitric oxide synthase (nNOS). Sci Rep. 2022;12(1):1701.
Ornithine Aminotransferase Inactivators
A remarkable difference that one fluorine atom confers on the mechanisms of inactivation of human ornithine aminotransferase by two cyclohexene analogues of γ-aminobutyric acid.
Zhu W, Doubleday PF, Catlin DS, Weerawarna PM, Butrin A, Shen S, Wawrzak Z, Kelleher NL, Liu D, Silverman RB. J. Am. Chem. Soc. 2020; 142: 4892-4903.
Turnover and inactivation mechanisms for (S)-3-amino-4,4-difluorocyclopent-1-enecarboxylic acid, a selective mechanism-based inactivator of human ornithine aminotransferase.
Shen S, Butrin A, Doubleday PF, Melani RD, Beaupre BA, Tavares MT, Ferreira GM, Kelleher NL, Moran GR, Liu D, Silverman RB. J. Am. Chem. Soc. 2021; 143: 8689-8703.
Remarkable and unexpected mechanism for (S)-3-amino-4-(difluoromethylenyl) cyclohex-1-ene-carboxylic acid as a selective inactivator of human ornithine aminotransferase.
Zhu W, Doubleday PF, Butrin A, Weerawarna PM, Melani R, Catlin DS, Dwight TA, Liu D, Kelleher NL, Silverman RB. J. Am. Chem. Soc. 2021; 143: 8193-8207.
Rational design, synthesis, and mechanism of (3S,4R)-3-amino-4-(difluoromethyl) cyclopent-1-ene-1-carboxylic acid: employing a second deprotonation strategy for selectivity of hOAT over GABA-AT.
Zhu W, Butrin A, Melani RD, Doubleday PF, Ferreira GM, Tavares MT, Habeeb Mohammad TS, Beaupre BA, Kelleher NL, Moran GR, Liu D, Silverman RB. J. Am. Chem. Soc., 2022; 144: 5629-5642.
Suppression of hepatocellular carcinoma by inhibition of overexpressed ornithine aminotransferase.
Zigmond E, Ben Ya'acov A, Lee H, Lichtenstein Y, Shalev Z, Smith Y, Zolotarov L, Ziv E, Kalman R, Le HV, Lu H, Silverman RB, Ilan Y. Suppression of Hepatocellular Carcinoma by Inhibition of Overexpressed Ornithine Aminotransferase. ACS Med Chem Lett. 2015;6(8):840-4.
Mechanism of inactivation of ornithine aminotransferase by (1S,3S)-3-amino-4-(hexafluoropropan-2-ylidenyl)cyclopentane-1-carboxylic acid
Moschitto MJ, Doubleday PF, Catlin DS, Kelleher NL, Liu D, Silverman RB. Mechanism of inactivation of ornithine aminotransferase by (1S,3S)-3-amino-4-(hexafluoropropan-2-ylidenyl)cyclopentane-1-carboxylic acid. J Am Chem Soc. 2019;141(27):10711-10721.
GABA Aminotransferase Inactivators
Mechanism of inactivation of gamma-aminobutyric acid aminotransferase by (1S,3S)-3-amino-4-difluoromethylenyl-1-cyclopentanoic acid (CPP-115)
Lee H, Doud EH, Wu R, Sanishvilli R, Juncosa JI, Liu D. Kelleher NL, Silverman RB. Mechanism of inactivation of γ-aminobutyric acid aminotransferase by (1S,3S)-3-amino-4-difluoromethylene-1-cyclopentanoic acid (CPP-115). J Am Chem Soc. 2015;137(7):2628-2640.
Design and mechanism of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid, a highly potent GABA aminotransferase inactivator for the treatment of addiction
Juncosa JI, Takaya K, Le HV, Moschitto MJ, Weerawarna PM, Mascarenhas R, Liu D, Dewey SL, Silverman RB. Design and mechanism of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid, a highly potent γ-aminobutyric acid aminotransferase inactivator for the treatment of addiction. J Am Chem Soc. 2018;140(6):2151-2164.
Genç, B.; Gautam, M.; Gözütok, Ö.; Dervishi, I.; Sanchez, S.; Goshu, G. M.; Koçak, N.; Xie, E.; Silverman, R. B.; Özdinler, P. H. Improving mitochondria and ER stability helps eliminate upper motor neuron degeneration that occurs due to mSOD1 toxicity and TDP-43 pathology. Clin. Transl. Med., 2021, 11, e336.
Chiral cyclohexane 1,3-diones as inhibitors of mutant SOD1-dependent protein aggregation for the treatment of ALS
NU-9 improves health of hSOD1 G93A mouse upper motor neurons in vitro, especially in combination with riluzole or edaravone
Mitochondria, ER, and nuclear membrane defects reveal early mechanisms for upper motor neuron vulnerability with respect to TDP-43 pathology
Incorporating upper motor neuron health in ALS drug discovery
Apical dendrite degeneration, a novel cellular pathology for Betz cells in ALS
Pathophysiological and diagnostic implications of cortical dysfunction in ALS
Treatment of amyotrophic lateral sclerosis: lessons learned from many failures
Moving forward in clinical trials for ALS: motor neurons lead the way please
eGFP expression under UCHL1 promoter genetically labels corticospinal motor neurons and a subpopulation of degeneration-resistant spinal motor neurons in an ALS mouse model
Zhang,Y.; Benmohamed, R.; Zhang, W.; Kim, J.; Edgerly, C.K.; Zhu,Y.; Morimoto, R.I.; Ferrante ,R.J.; Kirsch, D.R.; Silverman, R.B. Chiral Cyclohexane 1,3-Diones as Inhibitors of Mutant SOD1- Dependent Protein Aggregation for the Treatment of ALS. ACS Med. Chem. Lett. 2012, 3, 584−587
Genç, B.; Mukesh, G.; Benjamin, H.R.; Koçak, N.; Günay, A.; Gashaw, G.M.; Silverman, R.B.; Özdinler, P.H. NU‑9 improves health of hSOD1G93A mouse upper motor neurons in vitro, especially in combination with riluzole or edaravone. Scientific Reports 2022, 12:5383
Gautam, M.; Javier, J.H.; Kocak, N.; Rylaarsdam, L.E.; Kim, K.D.,; Bigio, E.H.; Özdinler, P.H. Mitochondria, ER, and nuclear membrane defects reveal early mechanisms for upper motor neuron vulnerability with respect to TDP‑43 pathology. Acta Neuropathol. 2019 January ; 137(1): 47–69.
Dervishi, I.; Özdinler, P.H. Incorporating upper motor neuron health in ALS drug discovery. Drug Discov. Today. 2018 March ; 23(3): 696–703.
Genç, B.; Jara, J.H.; Largrimas, A.K.B.; Pytel, P.; Roos, R.P.; Mesulam, M.M.; Geula, C.; Bigio, E.H.;Ozdinler, P.H. Apical dendrite degeneration, a novel cellular pathology for Betz cells in ALS. Scientific Reports 2017, 7:41765.
Geevasinga, N.; Özdinler, P.H.; Kiernan, M.C.; Vucic,S. Pathophysiological and diagnostic implications of cortical dysfunction in ALS. Nat Rev Neurol. 2016 Nov;12(11):651-661.
Özdinler, P.H.; Silverman, R.B. 2014. Treatment of Amyotrophic Lateral Sclerosis: Lessons Learned from Many Failures ACS Med. Chem. Lett. 2014, 5, 1179−1181
Genç, B.; Özdinler, P.H. 2014. Moving forward in clinical trials for ALS: motor neurons lead the way please. Drug Discov. Today. 2014 April ; 19(4): 441–449.
Yasvoina, M.B.; Genç, B.; Jara, J.H.; Sheets, P.L.; Quinlan, K.A.; Milosevic, A.; Shepherd, G.M.G.; Heckman, C.J.; Özdinler, P.H. eGFP Expression under UCHL1 Promoter Genetically Labels Corticospinal Motor Neurons and a Subpopulation of Degeneration-Resistant Spinal Motor Neurons in an ALS Mouse Model. J. Neurosci., May 1, 2013. 33(18):7890 –7904.
Ji, H.; Tan, S.; Igarashi, J.; Li, H.; Derrick, M.; Martásek, P.; Roman, L. J.; Vásquez-Vivar, J.; Poulos, T. L.; Silverman, R. B. Selective Neuronal Nitric Oxide Synthase Inhibitors for Prevention of Cerebral Palsy, Ann. Neurol. 2009, 65, 209-217.
Tong, S.; Cinelli, M. A.; Ibrahim, N.; Huang, H.; Silverman, R. B.; Yang, S. Inhibition of interferon-gamma-stimulated melanoma progression by targeting neuronal nitric oxide synthase (nNOS). Scientific Reports, 2022, 12, 1701.
Zigmond, E.; Ya'acov, A. B.; Lee, H.; Lichtenstein, Y.; Shalev, Z.; Smith, Y.; Zolotarov, L.; Ziv, E.; Kalman, R.; Le, H. V.; Lu, H.; Silverman, R. B.; Ilan, Y. Suppression of hepatocellular carcinoma by inhibition of overexpressed ornithine aminotransferase. ACS Med. Chem. Lett. 2015, 6, 840-844.
Moschitto, M. J.; Doubleday, P. F.; Catlin, D. S.; Kelleher, N. L.; Liu, D.; Silverman, R. B. Mechanism of inactivation of ornithine aminotransferase by (1S,3S)-3-amino-4-(hexafluoropropan-2-ylidenyl)cyclopentane-1-carboxylic acid. J. Am. Chem. Soc. 2019, 141, 10711-10721.
Lee, H.; Doud, E. H.; Wu, R.; Sanishvili, R.; Juncosa, J. I.; Liu, D.; Kelleher, N. L.; Silverman, R. B. Mechanism of inactivation of gamma-aminobutyric acid aminotransferase by (1S,3S)-3-amino-4-difluoromethylenyl-1-cyclopentanoic acid (CPP-115). J. Am. Chem. Soc. 2015, 137, 2628-2640.
Juncosa, J. I.; Takaya, K.; Le, H. V.; Moschitto, M. J.; Weerawarna, P. M.; Mascarenhas, R.; Liu, D.; Dewey, S. L.; Silverman, R. B. Design and mechanism of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid, a highly potent GABA aminotransferase inactivator for the treatment of addiction. J. Am. Chem. Soc. 2018, 140, 2151-2164.