Antimalarial activity of the anticancer histone deacetylase inhibitor SB939

Sumanadasa, Subathdrage D. M., Goodman, Christopher D., Lucke, Andrew J., Skinner-Adams, Tina, Sahama, Ishani, Haque, Ashraful, Do, Tram Anh, McFadden, Geoffrey I., Fairlie, David P. and Andrews, Katherine T. (2012) Antimalarial activity of the anticancer histone deacetylase inhibitor SB939. Antimicrobial Agents and Chemotherapy, 56 7: 3849-3856.


Author Sumanadasa, Subathdrage D. M.
Goodman, Christopher D.
Lucke, Andrew J.
Skinner-Adams, Tina
Sahama, Ishani
Haque, Ashraful
Do, Tram Anh
McFadden, Geoffrey I.
Fairlie, David P.
Andrews, Katherine T.
Title Antimalarial activity of the anticancer histone deacetylase inhibitor SB939
Journal name Antimicrobial Agents and Chemotherapy  (ERA 2012 Listed)    (ERA 2010 Rank A*)   Check publisher's open access policy
Publication date 2012-07
Sub-type Article
DOI 10.1128/AAC.00030-12
Volume number 56
Issue number 7
ISSN 0066-4804
1098-6596
Start page 3849
End page 3856
Total pages 8
Place of publication Washington, DC, United States
Publisher American Society for Microbiology
Collection year 2013
Language eng
Formatted abstract Histone deacetylase (HDAC) enzymes posttranslationally modify lysines on histone and nonhistone proteins and play crucial roles in epigenetic regulation and other important cellular processes. HDAC inhibitors (e.g., suberoylanilide hydroxamic acid [SAHA; also known as vorinostat]) are used clinically to treat some cancers and are under investigation for use against many other diseases. Development of new HDAC inhibitors for noncancer indications has the potential to be accelerated by piggybacking onto cancer studies, as several HDAC inhibitors have undergone or are undergoing clinical trials. One such compound, SB939, is a new orally active hydroxamate-based HDAC inhibitor with an improved pharmacokinetic profile compared to that of SAHA. In this study, the in vitro and in vivo antiplasmodial activities of SB939 were investigated. SB939 was found to be a potent inhibitor of the growth of Plasmodium falciparum asexual-stage parasites in vitro (50% inhibitory concentration [IC50], 100 to 200 nM), causing hyperacetylation of parasite histone and nonhistone proteins. In combination with the aspartic protease inhibitor lopinavir, SB939 displayed additive activity. SB939 also potently inhibited the in vitro growth of exoerythrocytic-stage Plasmodium parasites in liver cells (IC50, ∼150 nM), suggesting that inhibitor targeting to multiple malaria parasite life cycle stages may be possible. In an experimental in vivo murine model of cerebral malaria, orally administered SB939 significantly inhibited P. berghei ANKA parasite growth, preventing development of cerebral malaria-like symptoms. These results identify SB939 as a potent new antimalarial HDAC inhibitor and underscore the potential of investigating next-generation anticancer HDAC inhibitors as prospective new drug leads for treatment of malaria.
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

 
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Created: Tue, 17 Jul 2012, 08:25:56 EST by Lucy O'Brien on behalf of School of Chemistry & Molecular Biosciences