Masitinib (AB1010), a potent and selective tyrosine kinase inhibitor targeting KIT.
<h4>Background</h4>The stem cell factor receptor, KIT, is a target for the treatment of cancer, mastocytosis, and inflammatory diseases. Here, we characterise the in vitro and in vivo profiles of masitinib (AB1010), a novel phenylaminothiazole-type tyrosine kinase inhibitor that targets...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2009-09-01
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| Series: | PLoS ONE |
| Online Access: | https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/19789626/?tool=EBI |
| _version_ | 1819007013645975552 |
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| author | Patrice Dubreuil Sébastien Letard Marco Ciufolini Laurent Gros Martine Humbert Nathalie Castéran Laurence Borge Bérengère Hajem Anne Lermet Wolfgang Sippl Edwige Voisset Michel Arock Christian Auclair Phillip S Leventhal Colin D Mansfield Alain Moussy Olivier Hermine |
| author_facet | Patrice Dubreuil Sébastien Letard Marco Ciufolini Laurent Gros Martine Humbert Nathalie Castéran Laurence Borge Bérengère Hajem Anne Lermet Wolfgang Sippl Edwige Voisset Michel Arock Christian Auclair Phillip S Leventhal Colin D Mansfield Alain Moussy Olivier Hermine |
| author_sort | Patrice Dubreuil |
| collection | DOAJ |
| description | <h4>Background</h4>The stem cell factor receptor, KIT, is a target for the treatment of cancer, mastocytosis, and inflammatory diseases. Here, we characterise the in vitro and in vivo profiles of masitinib (AB1010), a novel phenylaminothiazole-type tyrosine kinase inhibitor that targets KIT.<h4>Methodology/principal findings</h4>In vitro, masitinib had greater activity and selectivity against KIT than imatinib, inhibiting recombinant human wild-type KIT with an half inhibitory concentration (IC(50)) of 200+/-40 nM and blocking stem cell factor-induced proliferation and KIT tyrosine phosphorylation with an IC(50) of 150+/-80 nM in Ba/F3 cells expressing human or mouse wild-type KIT. Masitinib also potently inhibited recombinant PDGFR and the intracellular kinase Lyn, and to a lesser extent, fibroblast growth factor receptor 3. In contrast, masitinib demonstrated weak inhibition of ABL and c-Fms and was inactive against a variety of other tyrosine and serine/threonine kinases. This highly selective nature of masitinib suggests that it will exhibit a better safety profile than other tyrosine kinase inhibitors; indeed, masitinib-induced cardiotoxicity or genotoxicity has not been observed in animal studies. Molecular modelling and kinetic analysis suggest a different mode of binding than imatinib, and masitinib more strongly inhibited degranulation, cytokine production, and bone marrow mast cell migration than imatinib. Furthermore, masitinib potently inhibited human and murine KIT with activating mutations in the juxtamembrane domain. In vivo, masitinib blocked tumour growth in mice with subcutaneous grafts of Ba/F3 cells expressing a juxtamembrane KIT mutant.<h4>Conclusions</h4>Masitinib is a potent and selective tyrosine kinase inhibitor targeting KIT that is active, orally bioavailable in vivo, and has low toxicity. |
| first_indexed | 2024-12-21T00:17:50Z |
| format | Article |
| id | doaj.art-63537d296c7e47bf89a26c076d6d1533 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-21T00:17:50Z |
| publishDate | 2009-09-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-63537d296c7e47bf89a26c076d6d15332022-12-21T19:22:11ZengPublic Library of Science (PLoS)PLoS ONE1932-62032009-09-0149e725810.1371/journal.pone.0007258Masitinib (AB1010), a potent and selective tyrosine kinase inhibitor targeting KIT.Patrice DubreuilSébastien LetardMarco CiufoliniLaurent GrosMartine HumbertNathalie CastéranLaurence BorgeBérengère HajemAnne LermetWolfgang SipplEdwige VoissetMichel ArockChristian AuclairPhillip S LeventhalColin D MansfieldAlain MoussyOlivier Hermine<h4>Background</h4>The stem cell factor receptor, KIT, is a target for the treatment of cancer, mastocytosis, and inflammatory diseases. Here, we characterise the in vitro and in vivo profiles of masitinib (AB1010), a novel phenylaminothiazole-type tyrosine kinase inhibitor that targets KIT.<h4>Methodology/principal findings</h4>In vitro, masitinib had greater activity and selectivity against KIT than imatinib, inhibiting recombinant human wild-type KIT with an half inhibitory concentration (IC(50)) of 200+/-40 nM and blocking stem cell factor-induced proliferation and KIT tyrosine phosphorylation with an IC(50) of 150+/-80 nM in Ba/F3 cells expressing human or mouse wild-type KIT. Masitinib also potently inhibited recombinant PDGFR and the intracellular kinase Lyn, and to a lesser extent, fibroblast growth factor receptor 3. In contrast, masitinib demonstrated weak inhibition of ABL and c-Fms and was inactive against a variety of other tyrosine and serine/threonine kinases. This highly selective nature of masitinib suggests that it will exhibit a better safety profile than other tyrosine kinase inhibitors; indeed, masitinib-induced cardiotoxicity or genotoxicity has not been observed in animal studies. Molecular modelling and kinetic analysis suggest a different mode of binding than imatinib, and masitinib more strongly inhibited degranulation, cytokine production, and bone marrow mast cell migration than imatinib. Furthermore, masitinib potently inhibited human and murine KIT with activating mutations in the juxtamembrane domain. In vivo, masitinib blocked tumour growth in mice with subcutaneous grafts of Ba/F3 cells expressing a juxtamembrane KIT mutant.<h4>Conclusions</h4>Masitinib is a potent and selective tyrosine kinase inhibitor targeting KIT that is active, orally bioavailable in vivo, and has low toxicity.https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/19789626/?tool=EBI |
| spellingShingle | Patrice Dubreuil Sébastien Letard Marco Ciufolini Laurent Gros Martine Humbert Nathalie Castéran Laurence Borge Bérengère Hajem Anne Lermet Wolfgang Sippl Edwige Voisset Michel Arock Christian Auclair Phillip S Leventhal Colin D Mansfield Alain Moussy Olivier Hermine Masitinib (AB1010), a potent and selective tyrosine kinase inhibitor targeting KIT. PLoS ONE |
| title | Masitinib (AB1010), a potent and selective tyrosine kinase inhibitor targeting KIT. |
| title_full | Masitinib (AB1010), a potent and selective tyrosine kinase inhibitor targeting KIT. |
| title_fullStr | Masitinib (AB1010), a potent and selective tyrosine kinase inhibitor targeting KIT. |
| title_full_unstemmed | Masitinib (AB1010), a potent and selective tyrosine kinase inhibitor targeting KIT. |
| title_short | Masitinib (AB1010), a potent and selective tyrosine kinase inhibitor targeting KIT. |
| title_sort | masitinib ab1010 a potent and selective tyrosine kinase inhibitor targeting kit |
| url | https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/19789626/?tool=EBI |
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