Lisa Sanderson1, Vanessa Yardley2, Simon L Croft1. 1. Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, Keppel Street, London WC1E 7HT, UK. 2. Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, Keppel Street, London WC1E 7HT, UK vanessa.yardley@lshtm.ac.uk.
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$), one approach to identifying new treatments for diseases like leishmaniasis is to evaluate drugs that are already registered for the treatment of other diseases. This paper describes the anti-leishmanial activities of 10 FDA-approved protein kinase inhibitors already available for the treatment of human cancers. METHODS: In vitro and in vivo models of Leishmania infection were used to evaluate the potency of selected protein kinase inhibitors. RESULTS: Sunitinib, sorafenib and lapatinib were identified as active against Leishmania donovani amastigotes in cultured murine macrophages with IC(50) values of 1.1, 3.7 and 2.5 μM, respectively, a level of potency similar to that of miltefosine (IC(50) = 1.0 μM), and were not toxic to mammalian cells. In addition, some of the protein kinase inhibitors were active against L. donovani in the BALB/c mouse model of infection; dosing on days 7-11 with a 50 mg/kg oral dose of sunitinib, lapatinib or sorafenib reduced liver amastigote burdens by 41%, 36% and 30%, respectively, compared with untreated control mice. Although less efficacious, sorafenib was also active in vitro against intracellular amastigotes of the cutaneous disease-causing species Leishmania amazonensis, Leishmania major and Leishmania mexicana. CONCLUSIONS: This study demonstrates in vivo anti-leishmanial activity of clinically used protein kinase inhibitors and provides further evidence of the potential of drug repurposing.
OBJECTIVES: There is an urgent need to develop new and effective treatments for poverty-related neglected diseases. In light of the time required to bring a new drug to market and the cost involved (10-15 years, >1 billion US$), 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 humancancers. 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: Diana Tegazzini; Rosario Díaz; Fernando Aguilar; Imanol Peña; Jesús L Presa; Vanessa Yardley; Julio J Martin; Jose M Coteron; Simon L Croft; Juan Cantizani Journal: Antimicrob Agents Chemother Date: 2016-05-23 Impact factor: 5.191
Authors: Imanol Peña; M Pilar Manzano; Juan Cantizani; Albane Kessler; Julio Alonso-Padilla; Ana I Bardera; Emilio Alvarez; Gonzalo Colmenarejo; Ignacio Cotillo; Irene Roquero; Francisco de Dios-Anton; Vanessa Barroso; Ana Rodriguez; David W Gray; Miguel Navarro; Vinod Kumar; Alexander Sherstnev; David H Drewry; James R Brown; Jose M Fiandor; J Julio Martin Journal: Sci Rep Date: 2015-03-05 Impact factor: 4.379
Authors: Carolina S Paladi; Danielle A M da Silva; Priscila D Motta; Daniel M Garcia; Daniela Teixeira; Ieda M Longo-Maugéri; Simone Katz; Clara L Barbiéri Journal: Front Microbiol Date: 2017-03-06 Impact factor: 5.640