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...
Guardado en:
| Autores principales: | , , , , , , , , , , , , , , , , |
|---|---|
| Formato: | article |
| Lenguaje: | EN |
| Publicado: |
Public Library of Science (PLoS)
2009
|
| Materias: | |
| Acceso en línea: | https://doaj.org/article/63537d296c7e47bf89a26c076d6d1533 |
| Etiquetas: |
Agregar Etiqueta
Sin Etiquetas, Sea el primero en etiquetar este registro!
|
| id |
oai:doaj.org-article:63537d296c7e47bf89a26c076d6d1533 |
|---|---|
| record_format |
dspace |
| spelling |
oai:doaj.org-article:63537d296c7e47bf89a26c076d6d15332021-11-25T06:20:03ZMasitinib (AB1010), a potent and selective tyrosine kinase inhibitor targeting KIT.1932-620310.1371/journal.pone.0007258https://doaj.org/article/63537d296c7e47bf89a26c076d6d15332009-09-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/19789626/?tool=EBIhttps://doaj.org/toc/1932-6203<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.Patrice DubreuilSébastien LetardMarco CiufoliniLaurent GrosMartine HumbertNathalie CastéranLaurence BorgeBérengère HajemAnne LermetWolfgang SipplEdwige VoissetMichel ArockChristian AuclairPhillip S LeventhalColin D MansfieldAlain MoussyOlivier HerminePublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 4, Iss 9, p e7258 (2009) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
Medicine R Science Q |
| spellingShingle |
Medicine R Science Q 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. |
| 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. |
| format |
article |
| 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 |
| title |
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_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_sort |
masitinib (ab1010), a potent and selective tyrosine kinase inhibitor targeting kit. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2009 |
| url |
https://doaj.org/article/63537d296c7e47bf89a26c076d6d1533 |
| work_keys_str_mv |
AT patricedubreuil masitinibab1010apotentandselectivetyrosinekinaseinhibitortargetingkit AT sebastienletard masitinibab1010apotentandselectivetyrosinekinaseinhibitortargetingkit AT marcociufolini masitinibab1010apotentandselectivetyrosinekinaseinhibitortargetingkit AT laurentgros masitinibab1010apotentandselectivetyrosinekinaseinhibitortargetingkit AT martinehumbert masitinibab1010apotentandselectivetyrosinekinaseinhibitortargetingkit AT nathaliecasteran masitinibab1010apotentandselectivetyrosinekinaseinhibitortargetingkit AT laurenceborge masitinibab1010apotentandselectivetyrosinekinaseinhibitortargetingkit AT berengerehajem masitinibab1010apotentandselectivetyrosinekinaseinhibitortargetingkit AT annelermet masitinibab1010apotentandselectivetyrosinekinaseinhibitortargetingkit AT wolfgangsippl masitinibab1010apotentandselectivetyrosinekinaseinhibitortargetingkit AT edwigevoisset masitinibab1010apotentandselectivetyrosinekinaseinhibitortargetingkit AT michelarock masitinibab1010apotentandselectivetyrosinekinaseinhibitortargetingkit AT christianauclair masitinibab1010apotentandselectivetyrosinekinaseinhibitortargetingkit AT phillipsleventhal masitinibab1010apotentandselectivetyrosinekinaseinhibitortargetingkit AT colindmansfield masitinibab1010apotentandselectivetyrosinekinaseinhibitortargetingkit AT alainmoussy masitinibab1010apotentandselectivetyrosinekinaseinhibitortargetingkit AT olivierhermine masitinibab1010apotentandselectivetyrosinekinaseinhibitortargetingkit |
| _version_ |
1718413805065601024 |