Fedratinib

Fedratinib
Names
IUPAC name
N-tert-Butyl-3-{5-methyl-2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenylamino]-pyrimidin-4-ylamino}-benzenesulfonamide
Other names
SAR302503; TG101348
Identifiers
3D model (JSmol)
Properties
C27H36N6O3S
Molar mass 524.68 g·mol−1
Density 1.247 ± 0.06 g/cm3
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Infobox references

Fedratinib (TG101348; SAR302503) is an orally available inhibitor of Janus kinase 2 (JAK-2) developed for the treatment of patients with myeloproliferative diseases including myelofibrosis. Fedratinib acts as a competitive inhibitor of protein kinase JAK-2 with IC50=6 nM; related kinases FLT3 and RET are also sensitive, with IC50=25 nM and IC50=17 nM, respectively. Significantly less activity was observed against other tyrosine kinases including JAK3 (IC50=169 nM).[1] In treated cells the inhibitor blocks downstream cellular signalling (JAK-STAT) leading to suppression of proliferation and induction of apoptosis.

Myelofibrosis is a myeloid malignancy associated with anemia, splenomegaly, and constitutional symptoms. Patients with myelofibrosis frequently harbor JAK-STAT activating mutations that are sensitive to TG101348. Phase I trial results focused on safety and efficacy of Fedratinib in patients with high- or intermediate-risk primary or post–polycythemia vera/essential thrombocythemia myelofibrosis have been published in 2011.[2]

Fedratinib was originally discovered at TargeGen. In 2010, Sanofi-Aventis acquired TargeGen and continued development of fedratinib until 2013. In 2016, Impact Biomedicines acquired the rights to fedratinib from Sanofi and continued its development for the treatment of myelofibrosis and polycythemia vera. In January 2018, Celgene acquired Impact Biomedicines.[3]

References

  1. ↑ Pardanani, A.; Hood, J.; Lasho, T.; Levine, R. L.; Martin, M. B.; Noronha, G.; Finke, C.; Mak, C. C.; Mesa, R.; Zhu, H.; Soll, R.; Gilliland, D. G.; Tefferi, A. (2007). "TG101209, a small molecule JAK2-selective kinase inhibitor potently inhibits myeloproliferative disorder-associated JAK2V617F and MPLW515L/K mutations". Leukemia. 21 (8): 1658–1668. doi:10.1038/sj.leu.2404750. PMID 17541402.
  2. ↑ Pardanani, A.; Gotlib, J. R.; Jamieson, C.; Cortes, J. E.; Talpaz, M.; Stone, R. M.; Silverman, M. H.; Gilliland, D. G.; Shorr, J.; Tefferi, A. (2011). "Safety and Efficacy of TG101348, a Selective JAK2 Inhibitor, in Myelofibrosis". Journal of Clinical Oncology. 29 (7): 789–796. doi:10.1200/JCO.2010.32.8021. PMC 4979099. PMID 21220608.
  3. ↑ "Celgene to Acquire Impact Biomedicines, Adding Fedratinib to Its Pipeline of Novel Therapies for Hematologic Malignancies (NASDAQ:CELG)". ir.celgene.com. Retrieved 2018-01-18.
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