John, Varghese, Ph.D.
  • Professor, Department of Neurology, David Geffen School of Medicine at UCLA

  • PI, Drug Discovery & Translational Laboratory, Department of Neurology, UCLA

  • Member, Alzheimer's Disease Program, Mary S. Easton Center for Alzheimer's Disease Research

  • Member, UCLA's Jonsson Comprehensive Cancer Center (JCCC)

John, Varghese, Ph.D.


Drug Discovery Laboratory
UCLA Department of Neurology
3131 Reed, 710 Westwood Plaza,
Los Angeles, CA 90095-1769
Tel: (310) 206-4345
Fax: (310) 794-3148
Email: This email address is being protected from spambots. You need JavaScript enabled to view it.



Medicinal Chemistry, Drug Discovery, Preclinical Development, Alzheimer's Disease.



Dr. John is an accomplished medicinal chemist and leads the Drug Discovery Laboratory (DDL) at the Department of Neurology at UCLA. Dr. John is a member of the Alzheimer’s Disease Program in the Mary S. Easton Center for Alzheimer's Disease. The DDL team consists of scientists and skilled technicians with basic science and drug development experience who have joined the lab to find effective, safe therapeutics for the treatment of Alzheimer's disease (AD). The DDL team identifies preclinical candidates and then establishes partnerships to progress these therapeutic agents from bench to bedside. Previously Dr. John was with Athena Neurosciences and Elan Pharmaceuticals for 18 years where he led a team of medicinal chemists developing drugs for central nervous system (CNS) diseases with a focus on AD. His work at Elan led to clinical candidates that went into advanced human trials. Dr. John is an inventor on over 100 pending or issued patents on compounds and analogs for CNS related targets.


Current Research

Development of therapeutics for Alzheimer's disease (AD) and other neurodegenerative disorders. Current focus of research in AD includes: (1) discovery of molecules that enhance the sAPPα levels in the brain, a candidate from this class DDL-110, is advancing into clinical trials in subjects with MCI due to AD; (2) discovery of molecules that reverse the ApoE4-mediated risk factor in AD; (3) discovery of APP-selective BACE inhibitors; (4) discovery of CRF receptor modulators that reduce p-Tau and reverse the Aβ induced memory deficits; and (5) discovery of molecules that prevent the intracellular APPΔC31 cleavage as potential therapeutics for AD.



  • Ph.D. Medicinal Chemistry, University of Minnesota, 1985.
  • Fellow, Dr. Josef Fried Laboratory, University of Chicago, 1985-1986.
  • Fellow, Dr. Carl Djerassi Laboratory, Stanford, 1986-1987.


Publications (selected peer-reviewed publications)

  • Sinha S, Anderson JP, Barbour R, Basi GS, Caccavello R, Davis D, Doan M, Dovey HF, N. Frigon N, Hong J, Jacobson-Croak K, Jewett N, Keim P, Knops J, Lieberburg I, Power M, Tan H, Tatsuno G, Tung J, Schenk D, Seubert P, Suomensaari SM, Wang S, Walker D, Zhao J, McConlogue L, John V. Purification and cloning of amyloid precursor protein β-secretase from human brain. Nature 1999;402:537-540. PMID: 10591214
  • Dovey HF, John V, Anderson, JP, Chen, LZ, Andrieu, PD, Fang, LY, Freedman, SB, Folmer, B, Goldbach, E, Holsztynska, EJ, Hu, KL, Johnson-Wood, KL, Kennedy, SL, Kholedenko, D, Knops, JE, Latimer, LH, Lee, M, Liao, Z, Lieberburg, IM, Motter, RN, Mutter, LC, Nietz, J, Quinn, KP, Sacchi, KL, Seubert, PA, Shopp, GM, Thorsett, ED, Tung, JS, Wu, J, Yang, S, Yin, CT, Schenk, DB, May, PC, Altstiel, LD, Bender, MH, Boggs, LN, Britton, TC, Clemens, JC, Czilli, DL, Dieckman-McGinty, DK, Droste, JJ, Fuson, KS, Gitter, BD, Hyslop, PA, Johnstone, EM, Li, WY, Little, SP, Mabry, TE, Miller, FD, Ni, B, Nissen, JS, Porter, WJ, Potts, BD, Reel, JK, Stephenson, D, Su, Y, Shipley, LA, Whitesitt, CA, Yin, T, and Audia, JE. Functional gamma-secretase inhibitors reduce beta-amyloid peptide levels in the brain. J Neurochemistry 2001;76(1):173-181. PMID: 11145990
  • John V. Human beta-secretase (BACE) and BACE inhibitors: progress report. Curr Top Med Chem 2006;6(6):569-578. PMID: 16712492
  • Maillard M, Hom RK, Benson TE, Moon JB, Mamo S, Bienkowski M, Tomasselli AG, Woods DD, Prince DB, Emmons TL, Tucker JT, Dappen MS, Brogley L, Thorsett ED, Jewett N, Sinha S, and John V. Design, synthesis, and crystal structure of hydroxyethyl secondary amine-based peptidomimetic inhibitors of human β-secretase. J Med Chem 2007;50(4):776-781. PMID: 17300163
  • Ellerby HM, Bredesen DE, Fujimura S, John V. Hunter-killer peptide (HKP) for targeted therapy. J Med Chem 2008;51(19):5887-5892. PMID: 18828573
  • Sealy JM, Truong AP, Tso L, Probst GD, Aquino J, Hom RK, Jagodzinska BM, Dressen D, Wone DW, Brogley L, John V, Tung JS, Pleiss MA, Tucker JA, Konradi AW, Dappen MS, Toth G, Pan H, Ruslim L, Miller J, Bova MP, Sinha S, Quinn KP, Sauer JM. Design and Synthesis of cell-potent BACE-1 inhibitors: structure-activity relationship of P1’ substituents. Bioorg Med Chem Lett 2009;19(20):6386-6391. PMID: 19811916
  • Bredesen DE, John V, Galvan V. Importance of the caspase cleavage site in amyloid-ß protein precursor. J Alzheimers Dis 2010;22(1):57-63. PMID: 20847422; PMCID: PMC3968071
  • Probst GD, Bowers S, Sealy JM, Stupi B, Dressen D, Jagodzinska BM, Aquino J, Gailunas A, Truong AP, Tso L, Xu YZ, Hom RK, John V, Tung JS, Pleiss MA, Tucker JA, Konradi AW, Sham HL, Jagodzinski J, Toth G, Brecht E, Yao N, Pan H, Lin M, Artis DR, Ruslim L, Bova MP, Sinha S, Yednock TA, Gauby S, Zmolek W, Quinn KP, Sauer JM. Design and synthesis of hydroxyethylamine (HEA) BACE-1 inhibitors: Structure-activity relationship of the aryl region. Bioorg Med Chem Lett 2010;20(20):6034-6039. PMID: 20822903
  • Truong AP, Probst GD, Aquino J, Fang L, Brogley L, Sealy JM, Hom RK, Tucker JA, John V, Tung JS, Pleiss MA, Konradi AW, Sham HL, Dappen MS, Tóth G, Yao N, Brecht E, Pan H, Artis DR, Ruslim L, Bova MP, Sinha S, Yednock TA, Zmolek W, Quinn KP, Sauer JM. Improving the permeability of the hydroxyethylamine BACE-1 inhibitors: structure-activity relationship of P2' substituents. Bioorg Med Chem Lett 2010;20(16):4789-4794. PMID: 20634069
  • Descamps O, Zhang Q, John V, Bredesen DE. Induction of the C-terminal proteolytic cleavage of AßPP by statins. J Alzheimers dis 2011;25(1):51-57. PMID: 21422530
  • Jin K, Mao XO, Xie L, John V, Greenberg DA. Pharmacological induction of neuroglobin expression. Pharmacology 2011;87(1-2):81-84. PMID: 21228614; PMCID: PMC3042117
  • Libeu CP, Poksay KS, John V, Bredesen DE. Structural and functional alterations in amyloid-β protein precursor induced by amyloid-β peptides. J Alzheimers Dis 2011;25(3):547-566. PMID: 21471643; PMCID: PMC4001850
  • Libeu CP, Descamps O, Zhang Q, John V, Bredesen DE. Altering APP proteolysis: Increasing sAPPalpha production by Targeting Dimerisation of APP Ectodomain. PLoS One 2012;7(6):e40027. PMID: 22768208; PMCID: PMC3386930
  • Rao RV, Descamps O, John V, Bredesen DE. Ayurvedic medicinal plants for Alzheimer’s disease : a review. Alzheimers Res Ther 2012;4(3):22. PMID: 22747839; PMCID: PMC3506936
  • Maccechini ML, Chang MY, Pan C, John V, Zetterberg H, Greig NH. Posiphen as a candidate drug to lower CSF amyloid precursor protein, amyloid-β peptide and tau levels: target engagement, tolerability and pharmacokinetics in humans. J Neurol Neurosurg Psychiatry 2012;83(9):894-902. PMID: 22791904; PMCID: PMC3415310
  • Descamps O, Spilman P, Zhang Q, Libeu CP, Poksay K, Gorostiza O, Campagna J, Jagodzinska B, Bredesen DE, John V. AβPP-selective BACE inhibitors (ASBI): novel class of therapeutic agents for Alzheimer's Disease. J Alzheimer's Disease 2013;37(2):343-355. PMID: 23948888; PMCID: PMC3971881
  • Ng RA, Sun M, Bowers S, Hom RK, Probst GD, John V, Fang LY, Maillard M, Gailunas A, Brogley L, Neitz RJ, Tung JS, Pleiss MA, Konradi AW, Sham HL, Dappen MS, Adler M, Yao N, Zmolek W, Nakamura D, Quinn KP, Sauer JM, Bova MP, Ruslim L, Artis DR, Yednock TA. Design and synthesis of hydroxyethylamine (HEA) BACE-1 inhibitors: prime side chromane-containing inhibitors. Bioorg Med Chem Lett 2013;23(16):4674-4679. PMID: 23856050
  • Theendakara V, Patent A, Libeu CP, Philpot B, Flores S, Descamps O, Poksay KS, Zhang Q, Cailing G, Hart M, John V, Rao RV, Bredesen DE. Neuroprotective sirtuin ratio reversed by ApoE4. Proceedings of the National Academy of Sciences of United States of America 2013;110(45):18303-18308. PMID: 24145446; PMCID: PMC3831497
  • Bredesen DE, John V. Next generation therapeutics for Alzheimer's disease. EMBO Mol Med 2013;5(6):795-798. PMID: 23703924; PMCID: PMC3779441
  • Zhang Q, Descamps O, Hart MJ, Poksay K, Spilman P, Kane D, Gorostiza O, John V, Bredesen DE. Paradoxical effect of TrkA inhibition in Alzheimer’s Disease. J Alzheimers Disease 2014;40(3):605-617. PMID: 24531152; PMCID: PMC4091737
  • Spilman P, Descamps O, Gorostiza O, Libeu CP, Poksay K, Matalis A, Patent A, Rao R, John V, Bredesen DB, The multi-functional drug Tropisetron binds APP and normalizes cognition in a murine Alzheimer's model. Brain Research 2014;1551:25-44. Issue Cover. doi:10.1016/j.brainres.2013.12.029. PMID: 24389031; PMCID: PMC4001856 [Available on 2015/3/10]
  • Alam MP, Jagodzinska B, Campagna J, Spilman P, John V. C-O bond formation in a microfluidic reactor: high yield SNAr substitution of heteroaryl chlorides. Tetrahedron Letter 2016;57(19):2059-2062. doi:10.1016/j.tetlet.2016.03.095


  • "BACE- A Lead Target for Orchestrated Therapy of Alzheimer’s Disease", Publisher: Wiley and Sons, 2010.


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