Masitinib

Masitinib is a tyrosine-kinase inhibitor used in the treatment of mast cell tumours in animals, specifically dogs.[1][2] Since its introduction in November 2008 it has been distributed under the commercial name Masivet. It has been available in Europe since the second part of 2009. Masitinib has been studied for several human conditions including melanoma, multiple myeloma, gastrointestinal cancer, pancreatic cancer, Alzheimer disease, multiple sclerosis, rheumatoid arthritis, mastocytosis, amyotrophic lateral sclerosis and COVID-19[3].[4][5][6]

Masitinib
Clinical data
Trade namesMasivet, Kinavet
AHFS/Drugs.comInternational Drug Names
ATC code
Identifiers
IUPAC name
  • 4-[(4-Methylpiperazin-1-yl)methyl]-N-(4-methyl-3-{[4-(pyridin-3-yl)-1,3-thiazol-2-yl]amino}phenyl)benzamide
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEMBL
PDB ligand
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC28H30N6OS
Molar mass498.65 g·mol−1
3D model (JSmol)
SMILES
  • O=C(c1ccc(cc1)CN2CCN(C)CC2)Nc3cc(c(cc3)C)Nc4nc(cs4)c5cccnc5
InChI
  • InChI=InChI=1S/C28H30N6OSc1-20-5-10-24(16-25(20)31-28-32-26(19-36-28)23-4-3-11-29-17-23)30-27(35)22-8-6-21(7-9-22)18-34-14-12-33(2)13-15-34h3-11,16-17,19H,12-15,18H2,1-2H3,(H,30,35)(H,31,32)
  • Key:WJEOLQLKVOPQFV-UHFFFAOYSA-N

Mechanism of action

Masitinib is a tyrosine kinase inhibitor which inhibits tyrosine kinases, enzymes responsible for the activation of many proteins by signal transduction cascades. Specifically, masitinib targets the receptor tyrosine kinase c-Kit which is found to be overexpressed or mutated in several types of cancer.[2][7] Masitinib is also additional targets, it also inhibits the platelet derived growth factor receptor (PDGFR), lymphocyte-specific protein tyrosine kinase (Lck), focal adhesion kinase (FAK) and fibroblast growth factor receptor 3 (FGFR3) as well as CSF1R.[8] [9]

Masitinib has been shown to block the replication of SARS-CoV-2 by inhibiting its main protease, 3CLpro. Masitinib showed >200-fold reduction in viral titers in the lungs and nose of mice infected with SARS-CoV-2.[6]

Clinical use

Masitinib was under investigation for the treatment of systemic mastocytosis (Masipro) but approval was denied in the EU in 2017 due to concerns "about the reliability of the study results" and major changes to the study design.[10][11]

European approval of masitinib for treatment of amyotrophic lateral sclerosis (Alsitek) was also refused in 2018.[12]

References
  1. Hahn KA, Ogilvie G, Oglivie G, Rusk T, Devauchelle P, Leblanc A, et al. (2008). "Masitinib is safe and effective for the treatment of canine mast cell tumors". Journal of Veterinary Internal Medicine. 22 (6): 1301–9. doi:10.1111/j.1939-1676.2008.0190.x. PMID 18823406.
  2. Information about Masivet at the European pharmacy agency website
  3. Drayman, Nir; DeMarco, Jennifer K.; Jones, Krysten A.; Azizi, Saara-Anne; Froggatt, Heather M.; Tan, Kemin; Maltseva, Natalia Ivanovna; Chen, Siquan; Nicolaescu, Vlad; Dvorkin, Steve; Furlong, Kevin (2021-07-20). "Masitinib is a broad coronavirus 3CL inhibitor that blocks replication of SARS-CoV-2". Science. 373 (6557): 931–936. Bibcode:2021Sci...373..931D. doi:10.1126/science.abg5827. ISSN 0036-8075. PMID 34285133.
  4. "Orphan designation EU/3/16/1722 for masitinib mesilate for the treatment of amyotrophic lateral sclerosis". European Medicines Agency. 2018-09-17.
  5. Folch J, Petrov D, Ettcheto M, Pedrós I, Abad S, Beas-Zarate C, et al. (June 2015). "Masitinib for the treatment of mild to moderate Alzheimer's disease". Expert Review of Neurotherapeutics. 15 (6): 587–96. doi:10.1586/14737175.2015.1045419. PMID 25961655. S2CID 39839943.
  6. Drayman, Nir; DeMarco, Jennifer K.; Jones, Krysten A.; Azizi, Saara-Anne; Froggatt, Heather M.; Tan, Kemin; Maltseva, Natalia Ivanovna; Chen, Siquan; Nicolaescu, Vlad; Dvorkin, Steve; Furlong, Kevin (2021-08-20). "Masitinib is a broad coronavirus 3CL inhibitor that blocks replication of SARS-CoV-2". Science. 373 (6557): 931–936. Bibcode:2021Sci...373..931D. doi:10.1126/science.abg5827. ISSN 0036-8075. PMID 34285133.
  7. Dubreuil, Patrice; Letard, Sébastien; Ciufolini, Marco; Gros, Laurent; Humbert, Martine; Castéran, Nathalie; Borge, Laurence; Hajem, Bérengère; Lermet, Anne; Sippl, Wolfgang; Voisset, Edwige; Arock, Michel; Auclair, Christian; Leventhal, Phillip S.; Mansfield, Colin D.; Moussy, Alain; Hermine, Olivier (2009). "Masitinib (AB1010), a Potent and Selective Tyrosine Kinase Inhibitor Targeting KIT". PLOS ONE. 4 (9): e7258. Bibcode:2009PLoSO...4.7258D. doi:10.1371/journal.pone.0007258. PMC 2746281. PMID 19789626.
  8. Gil da Costa RM (July 2015). "C-kit as a prognostic and therapeutic marker in canine cutaneous mast cell tumours: From laboratory to clinic". Veterinary Journal. 205 (1): 5–10. doi:10.1016/j.tvjl.2015.05.002. hdl:10216/103345. PMID 26021891.
  9. Trias, Emiliano; Ibarburu, Sofía; Barreto-Núñez, Romina; Babdor, Joël; MacIel, Thiago T.; Guillo, Matthias; Gros, Laurent; Dubreuil, Patrice; Díaz-Amarilla, Pablo; Cassina, Patricia; Martínez-Palma, Laura; Moura, Ivan C.; Beckman, Joseph S.; Hermine, Olivier; Barbeito, Luis (2016). "Post-paralysis tyrosine kinase inhibition with masitinib abrogates neuroinflammation and slows disease progression in inherited amyotrophic lateral sclerosis". Journal of Neuroinflammation. 13 (1): 177. doi:10.1186/s12974-016-0620-9. PMC 4940876. PMID 27400786.
  10. Refusal of the marketing authorisation for Masipro (masitinib). (PDF) EMA, 15. September 2017; abgerufen am 21. September 2017
  11. "Public Health - European Commission".
  12. "Public Health - European Commission".
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