title: Activity of anti-cancer protein kinase inhibitors against Leishmania spp.
abstract: OBJECTIVE
  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
  In vitro and in vivo models of Leishmania infection were used to evaluate the potency of selected protein kinase inhibitors.
  
  
  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.
authors.affiliation: Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, Keppel Street, London WC1E 7HT, UK.
authors.forename: Lisa
authors.initials: L
authors.lastname: Sanderson
authors.affiliation: Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, Keppel Street, London WC1E 7HT, UK vanessa.yardley@lshtm.ac.uk.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Yardley
authors.affiliation: Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, Keppel Street, London WC1E 7HT, UK.
authors.forename: Simon L
authors.initials: SL
authors.lastname: Croft
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D000981:Antiprotozoal Agents / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D058492:Drug Repositioning; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use; D020128:Inhibitory Concentration 50; D000077341:Lapatinib; D007891:Leishmania / Q000187:drug effects*; D007896:Leishmaniasis / Q000188:drug therapy*; D008807:Mice, Inbred BALB C; D009536:Niacinamide / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D010671:Phenylurea Compounds / Q000494:pharmacology / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D011758:Pyrroles / Q000494:pharmacology / Q000627:therapeutic use; D011799:Quinazolines / Q000494:pharmacology / Q000627:therapeutic use; D000077157:Sorafenib; D000077210:Sunitinib; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D000981:Antiprotozoal Agents; D007211:Indoles; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D011799:Quinazolines; D000077341:Lapatinib; D009536:Niacinamide; D000077157:Sorafenib; D000077210:Sunitinib
keywords: PP2; drug repurposing; lapatinib; sorafenib; sunitinib