Abstract | OBJECTIVES: There is an urgent need to develop new and effective treatments for poverty-related neglected diseases. In light of the time required to bring a new drug to market and the cost involved (10-15 years, >1 billion US$), one approach to identifying new treatments for diseases like leishmaniasis is to evaluate drugs that are already registered for the treatment of other diseases. This paper describes the anti-leishmanial activities of 10 FDA-approved protein kinase inhibitors already available for the treatment of human cancers. METHODS: RESULTS:
Sunitinib, sorafenib and lapatinib were identified as active against Leishmania donovani amastigotes in cultured murine macrophages with IC(50) values of 1.1, 3.7 and 2.5 μM, respectively, a level of potency similar to that of miltefosine (IC(50) = 1.0 μM), and were not toxic to mammalian cells. In addition, some of the protein kinase inhibitors were active against L. donovani in the BALB/c mouse model of infection; dosing on days 7-11 with a 50 mg/kg oral dose of sunitinib, lapatinib or sorafenib reduced liver amastigote burdens by 41%, 36% and 30%, respectively, compared with untreated control mice. Although less efficacious, sorafenib was also active in vitro against intracellular amastigotes of the cutaneous disease-causing species Leishmania amazonensis, Leishmania major and Leishmania mexicana. CONCLUSIONS: This study demonstrates in vivo anti-leishmanial activity of clinically used protein kinase inhibitors and provides further evidence of the potential of drug repurposing.
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Authors | Lisa Sanderson, Vanessa Yardley, Simon L Croft |
Journal | The Journal of antimicrobial chemotherapy
(J Antimicrob Chemother)
Vol. 69
Issue 7
Pg. 1888-91
(Jul 2014)
ISSN: 1460-2091 [Electronic] England |
PMID | 24668412
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | © The Author 2014. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: [email protected]. |
Chemical References |
- Antineoplastic Agents
- Antiprotozoal Agents
- Indoles
- Phenylurea Compounds
- Protein Kinase Inhibitors
- Pyrroles
- Quinazolines
- Lapatinib
- Niacinamide
- Sorafenib
- Sunitinib
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Topics |
- Animals
- Antineoplastic Agents
(pharmacology, therapeutic use)
- Antiprotozoal Agents
(pharmacology, therapeutic use)
- Disease Models, Animal
- Drug Repositioning
- Indoles
(pharmacology, therapeutic use)
- Inhibitory Concentration 50
- Lapatinib
- Leishmania
(drug effects)
- Leishmaniasis
(drug therapy)
- Mice, Inbred BALB C
- Niacinamide
(analogs & derivatives, pharmacology, therapeutic use)
- Phenylurea Compounds
(pharmacology, therapeutic use)
- Protein Kinase Inhibitors
(pharmacology, therapeutic use)
- Pyrroles
(pharmacology, therapeutic use)
- Quinazolines
(pharmacology, therapeutic use)
- Sorafenib
- Sunitinib
- Treatment Outcome
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