Alex Kazantsev, PhD, Huntington's and Parkinson's disease drug discovery research

Research Investigator Profile

Aleksey G. Kazantsev, PhD

Aleksey G. Kazantsev, PhD

  • Associate Professor in Neurology,
    Harvard Medical School
  • Drug Discovery Laboratory, MassGeneral Institute for Neurodegenerative Disease,
    Massachusetts General Hospital

 

 

Research Description

My laboratory is focused on discovery therapeutic agents for Huntington's and Parkinson's diseases using methods of high throughput screening, rational drug design, and medicinal chemistry lead optimization. We employ diverse approaches for small molecule targeting various pathophysiologic pathways of neurodegeneration. We conduct early stages of drug discovery in cellular models of neurodegeneration, and assess animal efficacy of identified promising molecules in disease rodent models. Our overall goal is to advance candidates emerged form these studies for therapeutic clinical development.

We have had early success using this strategy and discovered a novel compound, C2-8, that decreases aggregation in a cell-based assay of huntingtin aggregation.  The compound was found to improve behavior, decrease aggregation and decrease neuronal atrophy in a mouse model of Huntington's disease.

Recently we identified drugs, the inhibitors od SIRT2 decaetylase, protecting dopamine neurons from alpha-synuclein induced cell death in vitro and in vivo in models of Parkinson's disease. Human deacetylase SIRT2, one of seven human sirtuins, regulates acetylation of tubulin and thereby affects the cytoskeleton and neuronal plasticity.  Currently brain-permeable SIRT2 inhibitors start emerging from structure activity relationship studies. Efficacy animal trials are planned once the safety and tolerability of the new agents is explored.

 

Research interests

Huntington's and Parkinson's diseases

Research techniques

High throughput screening, rational drug design, and medicinal chemistry lead optimizatio

Diseases studied

Huntington's and Parkinson's diseases

Selected publications
  1. 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; 317:516-519.
  2.      
  3. 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.
  4. 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. 2006; 13: 765-770.
  5. Bodner, R.A., Fleming, O. T., 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.
  6. 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.
NCBI PubMed link NCBI PubMed Publications
E-mail address akazantsev@partners.org
Lab mailing address MassGeneral Institute for Neurodegenerative Disease
CNY B114-3300
114 16th Street
Charlestown, MA 02129
Lab website Kazantsev Drug Discovery Lab