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Kazantsev Drug Discovery Lab

The Kazantsev lab is focused on discovering therapeutic agents for Huntington's and Parkinson's diseases using high throughput screening, rational drug design, and medicinal chemistry lead optimization.
  • Lab Phone: 617-726-1278

The goal of drug discovery and pre-clinical development is to identify therapeutic agents that can slow or reverse neurodegeneration in experimental models, and develop these agents for clinical trials.  Our lab is focused on discovering 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.

neuroprotective effect of C2-8

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.

Aleksy Kazantsev, PhD

Principal Investigator

Aleksey G. (Alex) Kazantsev, PhD

  • Associate Professor in Neurology,
    Harvard Medical School
  • Assistant in Neuroscience,
    Massachusetts General Hospital

Research Interests: Huntington's and Parkinson's diseases

Research Techniques: High throughput screening, rational drug design, and medicinal chemistry lead optimization

Diseases Studied: Huntington's and Parkinson's diseases 

Research Scientists

  • Quinti, Luisa - Post Doc Fellow

Research Assistants & Technicians

  • Nobles, Johnathan - Lab Technician

neuroprotective effect of C2-8

Therapeutic targeting of aggregation pathway to reduce levels of neurotoxic intermediates

Drug discovery studies are underway to test small molecule inhibitors of polyglutamine aggregation. To date, structure-activity relationship (SAR) studies have been conducted on three scaffolds, yielding three candidate compounds. C2-8 rescued--in a dose-dependent manner--neurodegeneration of photoreceptor neurons in our lab’s Drosophila HD model. The results of these studies suggest a promising profile for possible administration to humans.

 

There are no open positions at this time.

  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. 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.
  3. 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.
  4. 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.
  5. 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 Publications