Aleksey Kazantsev, PhD

Associate Professor of Neurology, Harvard Medical School
Department of Neurology

Drug Discovery Laboratory
MassGeneral Institute for Neurodegenerative Disease

Our strategy on discovering therapeutic leads has been shaped by the early successes we had in designing diverse assays, in running high throughput screens and in testing therapies that work in relevant cell-based and animal models of neurodegeneration.

Using the high throughput screening approach, novel aggregation inhibitor C2-8 showed efficacy in genetic mouse models of Huntington's disease. Significant neuroprotection of striatal neurons, primarily affected in Huntington's disease, was observed in compound-treated R6/2 transgenic mice. Currently we are focused on improving animal efficacy of discovered therapeutic leads to develop clinical candidates.

Lead-compounds, identified in phenotypic high throughput screens, were employed for molecular target identification. Using that reverse-genetic approach we have identified a novel drug target for Parkinson's and Huntington's diseases. We demonstrated therapeutic potentials of pharmacological inhibition of sirtuin 2 modality in Parkinson's disease cell-based, primary neuronal, and fly models.

The identification SirT2 target has greatly expedited the process of drug discovery leading to discovery of potent and selective SirT2 inhibitors. To identify early clinical candidates we are currently in the process of lead-optimization for drug-like properties (ADMET).

Selected Publications

Outeiro, T.F., Kontopoulos, E., Steve Altman, S., Kufareva, I., Strathearn, K. E., . Amore, A. M., Volk, C. B., C. B., Maxwell, M. M., Rochet, J-V., McLean, P. J., Young, A. B., Abagyan, R., Feany, M. B., Hyman, B.T., Kazantsev, A. Sirtuin 2 Inhibitors Rescue Alpha-Synuclein-Mediated Toxicity in Models of Parkinson's Disease. Science, 2007, June 21 (ahead of print).

Abstract
http://www.sciencemag.org/cgi/content/abstract/1143780?ijkey=0lne8iz14/DEI&keytype=ref&siteid=sci

Reprint
http://www.sciencemag.org/cgi/rapidpdf/1143780?ijkey=0lne8iz14/DEI&keytype=ref&siteid=sci

Tiago, F.O., Grammatopoulos, T.N,. Altmann, S., Amore, A., Standaert, D. G., Hyman,, B. T., Kazantsev, A. G. Pharmacological Inhibition of PARP-1 Reduces Alpha-Synuclein- and MPP+-Induced Cytotoxicity in Parkinson's Disease In Vitro Models. Biochemical and Biophysical Research Communications. 2007, 357: 596-602.

Coufal. M., Maxwell, M.M, Russel, D.E., Amore, A.M., Altmann, S.M, ,Hollingsworth, Z.R., Young, A.B., Housman, D.E,., Kazantsev, A. G. Discovery of a Novel Small Molecule Targeting Selective Clearance of Mutant Huntingtin Fragments. Journal of Biomolecular Screening. 2007, 12: 351-360.

Altmann, S.M., Muryshev, A., Fossale, E., Maxwell, M.M., Norflus, F.N., Fox, J., Hersch, S.M., Young, A.B., MacDonald, M.E., Abagyan, R., Kazantsev, A. G. Discovery of a Bioactive Small Molecule Inhibitor of Poly (ADP-ribose) Polymerase (PARP1): Implications for Energy-Deficient Cells. Cell Chemistry & Biology (Cell Press) 2006, 13: 765-770.

Broom, W.J., Auwarter, K.E., Ni, J., Russel, D.E., Yeh, L.A., Maxwell, M.M., Glicksman, M., Kazantsev, A. G., Brown, R.H. Two Approaches to Drug discovery in SOD1-mediated ALS. Journal of Biomolecular Screening. 2006, 11:729-735.

Bodner, R.A., Outeiro, T. F., Altmann, S., Maxwell, M..M., Cho, S.H, Hyman, B.T., McLean, P.J., Young, A.B., Housman, D.E., Kazantsev, A.G. Pharmacological promotion of inclusion formation: a therapeutic approach for Huntington's and Parkinson's diseases Proc Natl Acad Sci U S A. 2006; 103: 4246-4251.

Zhang, X., Smith, D.L., Meriin, A.B., Engemann, S., Russel, D.E., Roark, M., Washington, S.L., Maxwell, M.M., Marsh, J.L., Thompson, L.M., Wanker, E.E., Young, A.B., Housman, D.E., Bates, G.P., Sherman, M.Y., Kazantsev, A.G. A potent small molecule inhibits polyglutamine aggregation in Huntington's disease neurons and suppresses neurodegeneration in vivo. Proc Natl Acad Sci U S A. 2005; 102:892-897.

Reviews, Chapters, and Editorials

Kazantsev, A.G., Hersch SM. Drug Targeting of Dysregulated Transcription in Huntington's Disease. Progress in Neurobiology (special issue on Chromatin Dysfunction in Huntington's Disease). 2007, in press (Available on-line February 23, 2007).

Kazantsev, A.G. Developing A Neuroprotective Therapy for Parkinson's and Huntington's Diseases. Expert Opinion. 2007, 17:159-172.

Bodner, R.A., Housman, D.E., Kazantsev, A.G. New directions for neurodegenerative disease therapy: using chemical compounds to boost the formation of mutant protein inclusions. (Review) Cell Cycle. 2006; 5: 1477-80.