WARNING: This product is for research use only, not for human or veterinary use.
MedKoo CAT#: 564142
CAS#: 1374744-69-0 (HCl hydrate)
Description: Fedratinib, also known as TG101348 and SAR302503, is a JAK2 inhibitor, is also an orally bioavailable, small-molecule, ATP-competitive inhibitor of Janus-associated kinase 2 (JAK2) with potential antineoplastic activity. JAK2 inhibitor TG101348 competes with JAK2 as well as the mutated form AK2V617F for ATP binding, which may result in inhibition of JAK2 activation, inhibition of the JAK-STAT signaling pathway, and the induction of tumor cell apoptosis. JAK2 is the most common mutated gene in bcr-abl-negative myeloproliferative disorders (MPDs); the mutated form JAK2V617F has a valine-to-phenylalanine modification at position 617 and plays a key role in tumor cell proliferation and survival.
MedKoo Cat#: 564142
Name: Fedratinib HCl hydrate
CAS#: 1374744-69-0 (HCl hydrate)
Chemical Formula: C27H40Cl2N6O4S
Exact Mass:
Molecular Weight: 615.62
Elemental Analysis: C, 52.68; H, 6.55; Cl, 11.52; N, 13.65; O, 10.40; S, 5.21
Related CAS #: 936091-26-8 (free base) 1374744-69-0 (HCl hydrate) 2468204-70-6 (HCl)
Synonym: Fedratinib dihydrochloride hydrate; SAR302503; SAR-302503; SAR 302503; TG101348; TG-101348; TG 101348;
IUPAC/Chemical Name: N-tert-Butyl-3-{5-methyl-2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenylamino]-pyrimidin-4-ylamino}-benzenesulfonamide dihydrochloride monohydrate
InChi Key: QAFZLTVOFJHYDF-UHFFFAOYSA-N
InChi Code: InChI=1S/C27H36N6O3S.2ClH.H2O/c1-20-19-28-26(30-21-10-12-23(13-11-21)36-17-16-33-14-5-6-15-33)31-25(20)29-22-8-7-9-24(18-22)37(34,35)32-27(2,3)4;;;/h7-13,18-19,32H,5-6,14-17H2,1-4H3,(H2,28,29,30,31);2*1H;1H2
SMILES Code: O=S(C1=CC=CC(NC2=NC(NC3=CC=C(OCCN4CCCC4)C=C3)=NC=C2C)=C1)(NC(C)(C)C)=O.[H]Cl.[H]Cl.[H]O[H]
Appearance: Solid powder
Purity: >98% (or refer to the Certificate of Analysis)
Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.
Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).
Solubility: Soluble in DMSO
Shelf Life: >3 years if stored properly
Drug Formulation: This drug may be formulated in DMSO
Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).
HS Tariff Code: 2934.99.9001
| Biological target: | Fedratinib hydrochloride hydrate (TG-101348 hydrochloride hydrate) is a potent, selective, ATP-competitive and orally active JAK2 inhibitor with IC50s of 3 nM for both JAK2 and JAK2V617F kinase. |
| In vitro activity: | Fedratinib-treated hMSC-TERT cells (3 µM) exhibited a significant reduction in ALP production, as evidenced by reduced cytochemical staining intensity (Figure 2B) compared with DMSO-vehicle treated control cells (Figure 2A). Moreover, the measurement of ALP activity at day 10 post-osteoblast differentiation induction was reduced compared with DMSO-vehicle treated control cells (Figure 2C). Fedratinib did not exert significant effects on hMSC-TERT cells viability at day 10 post-osteoblast differentiation induction (Figure 2D). Fedratinib-treated hMSC-TERT cells (3 µM) exhibited a significant decrease in mineralised matrix formation, as demonstrated by Alizarin red staining (Figure 3B), compared with DMSO-vehicle treated control cells (Figure 3A), which was associated with the significant downregulation of several osteoblast gene markers: ALP, ON, OC, RUNX2, OPN, and COL1A1 (Figure 4B). Reference: Molecules. 2021 Feb; 26(3): 606. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7866227/ |
| In vivo activity: | These studies demonstrate that TG101348 decreases atherosclerosis in Apoe−/− mice, likely by selective inhibition of hematopoietic JAK2 that results in suppression of excessive myelopoiesis driven by enhanced cell proliferation signaling in HSPCs and myeloid progenitors and reversal of HSPC expansion and leukocytosis. This suggests the possible translation of TG101348 therapy in reducing the risk of ACD in association with moderate myeloproliferation with or without JAK2 mutations. Reference: Cardiovasc Drugs Ther. 2020; 34(2): 145–152. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7125070/ |
| Solvent | Max Conc. mg/mL | Max Conc. mM | |
|---|---|---|---|
| Solubility | |||
| DMSO | 250.0 | 409.09 |
The following data is based on the product molecular weight 615.62 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.
| Concentration / Solvent Volume / Mass | 1 mg | 5 mg | 10 mg |
|---|---|---|---|
| 1 mM | 1.15 mL | 5.76 mL | 11.51 mL |
| 5 mM | 0.23 mL | 1.15 mL | 2.3 mL |
| 10 mM | 0.12 mL | 0.58 mL | 1.15 mL |
| 50 mM | 0.02 mL | 0.12 mL | 0.23 mL |
| Formulation protocol: | 1. AlMuraikhi N, Alaskar H, Binhamdan S, Alotaibi A, Kassem M, Alfayez M. JAK2 Inhibition by Fedratinib Reduces Osteoblast Differentiation and Mineralisation of Human Mesenchymal Stem Cells. Molecules. 2021 Jan 25;26(3):606. doi: 10.3390/molecules26030606. PMID: 33503825; PMCID: PMC7866227. 2. Pitroda SP, Stack ME, Liu GF, Song SS, Chen L, Liang H, Parekh AD, Huang X, Roach P, Posner MC, Weichselbaum RR, Khodarev NN. JAK2 Inhibitor SAR302503 Abrogates PD-L1 Expression and Targets Therapy-Resistant Non-small Cell Lung Cancers. Mol Cancer Ther. 2018 Apr;17(4):732-739. doi: 10.1158/1535-7163.MCT-17-0667. Epub 2018 Feb 21. PMID: 29467274. 3. Tang Y, Liu W, Wang W, Fidler T, Woods B, Levine RL, Tall AR, Wang N. Inhibition of JAK2 Suppresses Myelopoiesis and Atherosclerosis in Apoe-/- Mice. Cardiovasc Drugs Ther. 2020 Apr;34(2):145-152. doi: 10.1007/s10557-020-06943-9. PMID: 32086626; PMCID: PMC7125070. 4. Zhang L, Wang Y, Wu G, Rao L, Wei Y, Yue H, Yuan T, Yang P, Xiong F, Zhang S, Zhou Q, Chen Z, Li J, Mo BW, Zhang H, Xiong W, Wang CY. Blockade of JAK2 protects mice against hypoxia-induced pulmonary arterial hypertension by repressing pulmonary arterial smooth muscle cell proliferation. Cell Prolif. 2020 Feb;53(2):e12742. doi: 10.1111/cpr.12742. Epub 2020 Jan 14. PMID: 31943454; PMCID: PMC7046303. |
| In vitro protocol: | 1. AlMuraikhi N, Alaskar H, Binhamdan S, Alotaibi A, Kassem M, Alfayez M. JAK2 Inhibition by Fedratinib Reduces Osteoblast Differentiation and Mineralisation of Human Mesenchymal Stem Cells. Molecules. 2021 Jan 25;26(3):606. doi: 10.3390/molecules26030606. PMID: 33503825; PMCID: PMC7866227. 2. Pitroda SP, Stack ME, Liu GF, Song SS, Chen L, Liang H, Parekh AD, Huang X, Roach P, Posner MC, Weichselbaum RR, Khodarev NN. JAK2 Inhibitor SAR302503 Abrogates PD-L1 Expression and Targets Therapy-Resistant Non-small Cell Lung Cancers. Mol Cancer Ther. 2018 Apr;17(4):732-739. doi: 10.1158/1535-7163.MCT-17-0667. Epub 2018 Feb 21. PMID: 29467274. |
| In vivo protocol: | 1. Tang Y, Liu W, Wang W, Fidler T, Woods B, Levine RL, Tall AR, Wang N. Inhibition of JAK2 Suppresses Myelopoiesis and Atherosclerosis in Apoe-/- Mice. Cardiovasc Drugs Ther. 2020 Apr;34(2):145-152. doi: 10.1007/s10557-020-06943-9. PMID: 32086626; PMCID: PMC7125070. 2. Zhang L, Wang Y, Wu G, Rao L, Wei Y, Yue H, Yuan T, Yang P, Xiong F, Zhang S, Zhou Q, Chen Z, Li J, Mo BW, Zhang H, Xiong W, Wang CY. Blockade of JAK2 protects mice against hypoxia-induced pulmonary arterial hypertension by repressing pulmonary arterial smooth muscle cell proliferation. Cell Prolif. 2020 Feb;53(2):e12742. doi: 10.1111/cpr.12742. Epub 2020 Jan 14. PMID: 31943454; PMCID: PMC7046303. |
1: Blair HA. Fedratinib: First Approval. Drugs. 2019 Oct;79(15):1719-1725. doi: 10.1007/s40265-019-01205-x. Review. PubMed PMID: 31571162.
2: Singer JW, Al-Fayoumi S, Taylor J, Velichko S, O'Mahony A. Comparative phenotypic profiling of the JAK2 inhibitors ruxolitinib, fedratinib, momelotinib, and pacritinib reveals distinct mechanistic signatures. PLoS One. 2019 Sep 27;14(9):e0222944. doi: 10.1371/journal.pone.0222944. eCollection 2019. PubMed PMID: 31560729; PubMed Central PMCID: PMC6764664.
3: Fedratinib Becomes New Option in Myelofibrosis. Cancer Discov. 2019 Oct;9(10):1332. doi: 10.1158/2159-8290.CD-NB2019-102. Epub 2019 Aug 30. PubMed PMID: 31471287.
4: Ogasawara K, Zhou S, Krishna G, Palmisano M, Li Y. Population pharmacokinetics of fedratinib in patients with myelofibrosis, polycythemia vera, and essential thrombocythemia. Cancer Chemother Pharmacol. 2019 Oct;84(4):891-898. doi: 10.1007/s00280-019-03929-9. Epub 2019 Aug 23. PubMed PMID: 31444617; PubMed Central PMCID: PMC6768916.
5: Chen D, Zhang F, Wang J, He H, Duan S, Zhu R, Chen C, Yin L, Chen Y. Biodegradable Nanoparticles Mediated Co-delivery of Erlotinib (ELTN) and Fedratinib (FDTN) Toward the Treatment of ELTN-Resistant Non-small Cell Lung Cancer (NSCLC) via Suppression of the JAK2/STAT3 Signaling Pathway. Front Pharmacol. 2018 Nov 13;9:1214. doi: 10.3389/fphar.2018.01214. eCollection 2018. PubMed PMID: 30483119; PubMed Central PMCID: PMC6242943.
6: Correction to "Interaction of 2,4-Diaminopyrimidine Containing Drugs Including Fedratinib and Trimethoprim with Thiamine Transporters". Drug Metab Dispos. 2017 Nov;45(11):1146-1147. doi: 10.1124/dmd.116.073338err. PubMed PMID: 28974558.
7: Harrison CN, Schaap N, Vannucchi AM, Kiladjian JJ, Tiu RV, Zachee P, Jourdan E, Winton E, Silver RT, Schouten HC, Passamonti F, Zweegman S, Talpaz M, Lager J, Shun Z, Mesa RA. Janus kinase-2 inhibitor fedratinib in patients with myelofibrosis previously treated with ruxolitinib (JAKARTA-2): a single-arm, open-label, non-randomised, phase 2, multicentre study. Lancet Haematol. 2017 Jul;4(7):e317-e324. doi: 10.1016/S2352-3026(17)30088-1. Epub 2017 Jun 8. PubMed PMID: 28602585.
8: Hazell AS, Afadlal S, Cheresh DA, Azar A. Treatment of rats with the JAK-2 inhibitor fedratinib does not lead to experimental Wernicke's encephalopathy. Neurosci Lett. 2017 Mar 6;642:163-167. doi: 10.1016/j.neulet.2017.01.041. Epub 2017 Jan 18. PubMed PMID: 28109775.
9: Giacomini MM, Hao J, Liang X, Chandrasekhar J, Twelves J, Whitney JA, Lepist EI, Ray AS. Interaction of 2,4-Diaminopyrimidine-Containing Drugs Including Fedratinib and Trimethoprim with Thiamine Transporters. Drug Metab Dispos. 2017 Jan;45(1):76-85. Epub 2016 Nov 1. Erratum in: Drug Metab Dispos. 2017 Nov;45(11):1146-1147. PubMed PMID: 27803021.
10: Zhang M, Xu C, Ma L, Shamiyeh E, Yin J, von Moltke LL, Smith WB. Effect of food on the bioavailability and tolerability of the JAK2-selective inhibitor fedratinib (SAR302503): Results from two phase I studies in healthy volunteers. Clin Pharmacol Drug Dev. 2015 Jul;4(4):315-21. doi: 10.1002/cpdd.161. Epub 2014 Oct 27. PubMed PMID: 27136912.
11: Jamieson C, Hasserjian R, Gotlib J, Cortes J, Stone R, Talpaz M, Thiele J, Rodig S, Pozdnyakova O. Effect of treatment with a JAK2-selective inhibitor, fedratinib, on bone marrow fibrosis in patients with myelofibrosis. J Transl Med. 2015 Sep 10;13:294. doi: 10.1186/s12967-015-0644-4. PubMed PMID: 26357842; PubMed Central PMCID: PMC4566296.
12: Pardanani A, Tefferi A, Jamieson C, Gabrail NY, Lebedinsky C, Gao G, Liu F, Xu C, Cao H, Talpaz M. A phase 2 randomized dose-ranging study of the JAK2-selective inhibitor fedratinib (SAR302503) in patients with myelofibrosis. Blood Cancer J. 2015 Aug 7;5:e335. doi: 10.1038/bcj.2015.63. PubMed PMID: 26252788; PubMed Central PMCID: PMC4558588.
13: Pardanani A, Harrison C, Cortes JE, Cervantes F, Mesa RA, Milligan D, Masszi T, Mishchenko E, Jourdan E, Vannucchi AM, Drummond MW, Jurgutis M, Kuliczkowski K, Gheorghita E, Passamonti F, Neumann F, Patki A, Gao G, Tefferi A. Safety and Efficacy of Fedratinib in Patients With Primary or Secondary Myelofibrosis: A Randomized Clinical Trial. JAMA Oncol. 2015 Aug;1(5):643-51. doi: 10.1001/jamaoncol.2015.1590. PubMed PMID: 26181658.
14: Polverelli N, Catani L, Vianelli N, Baccarani M, Cavo M, Palandri F. Ruxolitinib- but not fedratinib-induced extreme thrombocytosis: the combination therapy with hydroxyurea and ruxolitinib is effective in reducing platelet count and splenomegaly/constitutional symptoms. Ann Hematol. 2015 Sep;94(9):1585-7. doi: 10.1007/s00277-015-2397-9. Epub 2015 May 16. PubMed PMID: 25975976.
15: Zhang Q, Zhang Y, Diamond S, Boer J, Harris JJ, Li Y, Rupar M, Behshad E, Gardiner C, Collier P, Liu P, Burn T, Wynn R, Hollis G, Yeleswaram S. The Janus kinase 2 inhibitor fedratinib inhibits thiamine uptake: a putative mechanism for the onset of Wernicke's encephalopathy. Drug Metab Dispos. 2014 Oct;42(10):1656-62. doi: 10.1124/dmd.114.058883. Epub 2014 Jul 25. PubMed PMID: 25063672.
16: Zhang M, Xu CR, Shamiyeh E, Liu F, Yin JY, von Moltke LL, Smith WB. A randomized, placebo-controlled study of the pharmacokinetics, pharmacodynamics, and tolerability of the oral JAK2 inhibitor fedratinib (SAR302503) in healthy volunteers. J Clin Pharmacol. 2014 Apr;54(4):415-21. doi: 10.1002/jcph.218. Epub 2013 Nov 16. PubMed PMID: 24165976.
